Discovery of Dengue Virus Inhibitors

Adib    Afandi    Abdullah; Yean    Kee    Lee; Sek    Peng    Chin; See    Khai    Lim; Vannajan    Sanghiran    Lee; Rozana       Othman; Shatrah       Othman; Noorsaadah    Abdul    Rahman; Rohana       Yusof; Choon    Han    Heh
doi:10.2174/0929867326666181204155336
Abstract

To date, there is still no approved anti-dengue agent to treat dengue infection in the market. Although the only licensed dengue vaccine, Dengvaxia is available, its protective efficacy against serotypes 1 and 2 of dengue virus was reported to be lower than serotypes 3 and 4. Moreover, according to WHO, the risk of being hospitalized and having severe dengue increased in seronegative individuals after they received Dengvaxia vaccination. Nevertheless, various studies had been carried out in search of dengue virus inhibitors. These studies focused on the structural (C, prM, E) and non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5) of dengue virus as well as host factors as drug targets. Hence, this article provides an overall up-to-date review of the discovery of dengue virus inhibitors that are only targeting the structural and non-structural viral proteins as drug targets.
Keywords: Drug discovery, dengue virus, virus inhibitors, structural proteins, non-structural proteins, drug targets.
« Previous Next »
[1] 
Shepard, D.S.; Coudeville, L.; Halasa, Y.A.; Zambrano, B.; Dayan, G.H. Economic impact of dengue illness in the Americas. Am. J. Trop. Med. Hyg.,  2011, 84(2), 200-207.
[http://dx.doi.org/10.4269/ajtmh.2011.10-0503] [PMID:  21292885] 
[2] 
Shepard, D.S.; Undurraga, E.A.; Halasa, Y.A. Economic and disease burden of dengue in Southeast Asia. PLoS Negl. Trop. Dis.,  2013, 7(2), e2055.
[http://dx.doi.org/10.1371/journal.pntd.0002055] [PMID:  23437406] 
[3] 

World Health Organization Dengue: guidelines for diagnosis, treatment, prevention and control: new edition, 2009.
[4] 
Bhatt, S.; Gething, P.W.; Brady, O.J.; Messina, J.P.; Farlow, A.W.; Moyes, C.L.; Drake, J.M.; Brownstein, J.S.; Hoen, A.G.; Sankoh, O.; Myers, M.F.; George, D.B.; Jaenisch, T.; Wint, G.R.; Simmons, C.P.; Scott, T.W.; Farrar, J.J.; Hay, S.I. The global distribution and burden of dengue. Nature,  2013, 496(7446), 504-507.
[http://dx.doi.org/10.1038/nature12060] [PMID:  23563266] 
[5] 
Shepard, D.S.; Lees, R.; Ng, C.W.; Undurraga, E.A.; Halasa, Y.; Lum, L. burden of dengue in malaysia Report from a collaboration between universities and the ministry of health of malaysia., 2013.
[6] 
Gubler, D.; Kuno, G. Dengue and dengue hemorrhagic fever: its history and resurgence as a global public health problem. Dengue and dengue hemorrhagic fever; CAB international: London, United Kingdom, 1997, pp. 1-22.
[http://dx.doi.org/10.1016/B978-0-443-06668-9.50077-6] 
[7] 
Wilder-Smith, A.; Gubler, D.J. Geographic expansion of dengue: the impact of international travel. Med. Clin. North Am.,  2008, 92(6), 1377-1390, x..
[http://dx.doi.org/10.1016/j.mcna.2008.07.002] [PMID:  19061757] 
[8] 
Gubler, D.J. Dengue, urbanization and globalization: the unholy trinity of the 21st century. Trop. Med. Health,  2011, 39(4)(Suppl.), 3-11.
[http://dx.doi.org/10.2149/tmh.2011-S05] [PMID:  22500131] 
[9] 
Smith, C.E. The history of dengue in tropical Asia and its probable relationship to the mosquito Aedes aegypti. J. Trop. Med. Hyg.,  1956, 59(10), 243-251.
[PMID:  13368255] 
[10] 
Hirsch, A. Dengue, a comparatively new disease: its symptoms. handbook of geographical and historical pathology,; , 1883, 59, pp. 55-81.
[11] 
Ehrenkranz, N.J.; Ventura, A.K.; Cuadrado, R.R.; Pond, W.L.; Porter, J.E. Pandemic dengue in Caribbean countries and the southern United States--past, present and potential problems. N. Engl. J. Med.,  1971, 285(26), 1460-1469.
[http://dx.doi.org/10.1056/NEJM197112232852606] [PMID:  4941592] 
[12] 
Wang, E.; Ni, H.; Xu, R.; Barrett, A.D.; Watowich, S.J.; Gubler, D.J.; Weaver, S.C. Evolutionary relationships of endemic/epidemic and sylvatic dengue viruses. J. Virol.,  2000, 74(7), 3227-3234.
[http://dx.doi.org/10.1128/JVI.74.7.3227-3234.2000] [PMID:  10708439] 
[13] 
Holmes, E.C.; Twiddy, S.S. The origin, emergence and evolutionary genetics of dengue virus. Infect. Genet. Evol.,  2003, 3(1), 19-28.
[http://dx.doi.org/10.1016/S1567-1348(03)00004-2] [PMID:  12797969] 
[14] 
Weaver, S.C.; Barrett, A.D. Transmission cycles, host range, evolution and emergence of arboviral disease. Nat. Rev. Microbiol.,  2004, 2(10), 789-801.
[http://dx.doi.org/10.1038/nrmicro1006] [PMID:  15378043] 
[15] 
Midgley, C.M.; Bajwa-Joseph, M.; Vasanawathana, S.; Limpitikul, W.; Wills, B.; Flanagan, A.; Waiyaiya, E.; Tran, H.B.; Cowper, A.E.; Chotiyarnwong, P.; Grimes, J.M.; Yoksan, S.; Malasit, P.; Simmons, C.P.; Mongkolsapaya, J.; Screaton, G.R. An in-depth analysis of original antigenic sin in dengue virus infection. J. Virol.,  2011, 85(1), 410-421.
[http://dx.doi.org/10.1128/JVI.01826-10] [PMID:  20980526] 
[16] 
Halstead, S.B.; Rojanasuphot, S.; Sangkawibha, N. Original antigenic sin in dengue. Am. J. Trop. Med. Hyg.,  1983, 32(1), 154-156.
[http://dx.doi.org/10.4269/ajtmh.1983.32.154] [PMID:  6824120] 
[17] 
Halstead, S.B.; O’Rourke, E.J. Antibody-enhanced dengue virus infection in primate leukocytes. Nature,  1977, 265(5596), 739-741.
[http://dx.doi.org/10.1038/265739a0] [PMID:  404559] 
[18] 
Halstead, S.B.; O’Rourke, E.J. Dengue viruses and mononuclear phagocytes. I. Infection enhancement by non-neutralizing antibody. J. Exp. Med.,  1977, 146(1), 201-217.
[http://dx.doi.org/10.1084/jem.146.1.201] [PMID:  406347] 
[19] 
Goncalvez, A.P.; Engle, R.E.; St Claire, M.; Purcell, R.H.; Lai, C.-J. Monoclonal antibody-mediated enhancement of dengue virus infection in vitro and in vivo and strategies for prevention. Proc. Natl. Acad. Sci. USA,  2007, 104(22), 9422-9427.
[http://dx.doi.org/10.1073/pnas.0703498104] [PMID:  17517625] 
[20] 
Modis, Y.; Ogata, S.; Clements, D.; Harrison, S.C. A ligand-binding pocket in the dengue virus envelope glycoprotein. Proc. Natl. Acad. Sci. USA,  2003, 100(12), 6986-6991.
[http://dx.doi.org/10.1073/pnas.0832193100] [PMID:  12759475] 
[21] 
Modis, Y.; Ogata, S.; Clements, D.; Harrison, S.C. Structure of the dengue virus envelope protein after membrane fusion. Nature,  2004, 427(6972), 313-319.
[http://dx.doi.org/10.1038/nature02165] [PMID:  14737159] 
[22] 
Bressanelli, S.; Stiasny, K.; Allison, S.L.; Stura, E.A.; Duquerroy, S.; Lescar, J.; Heinz, F.X.; Rey, F.A. Structure of a flavivirus envelope glycoprotein in its low-pH-induced membrane fusion conformation. EMBO J.,  2004, 23(4), 728-738.
[http://dx.doi.org/10.1038/sj.emboj.7600064] [PMID:  14963486] 
[23] 
Cahour, A.; Falgout, B.; Lai, C.J. Cleavage of the dengue virus polyprotein at the NS3/NS4A and NS4B/NS5 junctions is mediated by viral protease NS2B-NS3, whereas NS4A/NS4B may be processed by a cellular protease. J. Virol.,  1992, 66(3), 1535-1542.
[http://dx.doi.org/10.1128/JVI.66.3.1535-1542.1992] [PMID:  1531368] 
[24] 
Amberg, S.M.; Nestorowicz, A.; McCourt, D.W.; Rice, C.M. NS2B-3 proteinase-mediated processing in the yellow fever virus structural region: in vitro and in vivo studies. J. Virol.,  1994, 68(6), 3794-3802.
[http://dx.doi.org/10.1128/JVI.68.6.3794-3802.1994] [PMID:  8189517] 
[25] 
Falgout, B.; Markoff, L. Evidence that flavivirus NS1-NS2A cleavage is mediated by a membrane-bound host protease in the endoplasmic reticulum. J. Virol.,  1995, 69(11), 7232-7243.
[http://dx.doi.org/10.1128/JVI.69.11.7232-7243.1995] [PMID:  7474145] 
[26] 
Falgout, B.; Pethel, M.; Zhang, Y.M.; Lai, C.J. Both nonstructural proteins NS2B and NS3 are required for the proteolytic processing of dengue virus nonstructural proteins. J. Virol.,  1991, 65(5), 2467-2475.
[http://dx.doi.org/10.1128/JVI.65.5.2467-2475.1991] [PMID:  2016768] 
[27] 
Uchil, P.D.; Satchidanandam, V. Architecture of the flaviviral replication complex. Protease, nuclease, and detergents reveal encasement within double-layered membrane compartments. J. Biol. Chem.,  2003, 278(27), 24388-24398.
[http://dx.doi.org/10.1074/jbc.M301717200] [PMID:  12700232] 
[28] 
Jiang, L.; Yao, H.; Duan, X.; Lu, X.; Liu, Y. Polypyrimidine tract-binding protein influences negative strand RNA synthesis of dengue virus. Biochem. Biophys. Res. Commun.,  2009, 385(2), 187-192.
[http://dx.doi.org/10.1016/j.bbrc.2009.05.036] [PMID:  19450550] 
[29] 
Bartholomeusz, A.I.; Wright, P.J. Synthesis of dengue virus RNA in vitro: initiation and the involvement of proteins NS3 and NS5. Arch. Virol.,  1993, 128(1-2), 111-121.
[http://dx.doi.org/10.1007/BF01309792] [PMID:  8418788] 
[30] 
Li, H.; Clum, S.; You, S.; Ebner, K.E.; Padmanabhan, R. The serine protease and RNA-stimulated nucleoside triphosphatase and RNA helicase functional domains of dengue virus type 2 NS3 converge within a region of 20 amino acids. J. Virol.,  1999, 73(4), 3108-3116.
[http://dx.doi.org/10.1128/JVI.73.4.3108-3116.1999] [PMID:  10074162] 
[31] 
Egloff, M.P.; Benarroch, D.; Selisko, B.; Romette, J.L.; Canard, B. An RNA cap (nucleoside-2′-O-)-methyltransferase in the flavivirus RNA polymerase NS5: crystal structure and functional characterization. EMBO J.,  2002, 21(11), 2757-2768.
[http://dx.doi.org/10.1093/emboj/21.11.2757] [PMID:  12032088] 
[32] 
Issur, M.; Geiss, B.J.; Bougie, I.; Picard-Jean, F.; Despins, S.; Mayette, J.; Hobdey, S.E.; Bisaillon, M. The flavivirus NS5 protein is a true RNA guanylyltransferase that catalyzes a two-step reaction to form the RNA cap structure. RNA,  2009, 15(12), 2340-2350.
[http://dx.doi.org/10.1261/rna.1609709] [PMID:  19850911] 
[33] 
Yu, I-M.; Zhang, W.; Holdaway, H.A.; Li, L.; Kostyuchenko, V.A.; Chipman, P.R.; Kuhn, R.J.; Rossmann, M.G.; Chen, J. Structure of the immature dengue virus at low pH primes proteolytic maturation. Science,  2008, 319(5871), 1834-1837.
[http://dx.doi.org/10.1126/science.1153264] [PMID:  18369148] 
[34] 
Heinz, F. X.; Allison, S. L. Structures and mechanisms in flavivirus fusion., 2000.
[http://dx.doi.org/10.1016/s0065-3527(00)55005-2] 
[35] 
Yu, I.M.; Holdaway, H.A.; Chipman, P.R.; Kuhn, R.J.; Rossmann, M.G.; Chen, J. Association of the pr peptides with dengue virus at acidic pH blocks membrane fusion. J. Virol.,  2009, 83(23), 12101-12107.
[http://dx.doi.org/10.1128/JVI.01637-09] [PMID:  19759134] 
[36] 
Simmons, C.P.; Farrar, J.J.; Nguyen, V.; Wills, B. Dengue. N. Engl. J. Med.,  2012, 366(15), 1423-1432.
[http://dx.doi.org/10.1056/NEJMra1110265] [PMID:  22494122] 
[37] 
Organization, W.H. Research, S. P. f.; Diseases, T. i. T.; Diseases, W. H. O. D. o. C. o. N. T.; Epidemic, W. H. O.; Alert, P., Dengue: guidelines for diagnosis, treatment, prevention and control; World Health Organization, 2009. 
[38] 
Sanofi, P. Sanofi pasteur dengue vaccine approved in Costa Rica., http://www.sanofipasteur.ca/node/49201
[39] 
Villar, L.; Dayan, G.H.; Arredondo-García, J.L.; Rivera, D.M.; Cunha, R.; Deseda, C.; Reynales, H.; Costa, M.S.; Morales-Ramírez, J.O.; Carrasquilla, G.; Rey, L.C.; Dietze, R.; Luz, K.; Rivas, E.; Miranda Montoya, M.C.; Cortés Supelano, M.; Zambrano, B.; Langevin, E.; Boaz, M.; Tornieporth, N.; Saville, M.; Noriega, F.; Group, C.Y.D.S. CYD15 Study Group Efficacy of a tetravalent dengue vaccine in children in Latin America. N. Engl. J. Med.,  2015, 372(2), 113-123.
[http://dx.doi.org/10.1056/NEJMoa1411037] [PMID:  25365753] 
[40] 
Capeding, M.R.; Tran, N.H.; Hadinegoro, S.R.; Ismail, H.I.; Chotpitayasunondh, T.; Chua, M.N.; Luong, C.Q.; Rusmil, K.; Wirawan, D.N.; Nallusamy, R.; Pitisuttithum, P.; Thisyakorn, U.; Yoon, I.K.; van der Vliet, D.; Langevin, E.; Laot, T.; Hutagalung, Y.; Frago, C.; Boaz, M.; Wartel, T.A.; Tornieporth, N.G.; Saville, M.; Bouckenooghe, A.; Group, C.Y.D.S. CYD14 Study Group. Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observer-masked, placebo-controlled trial. Lancet,  2014, 384(9951), 1358-1365.
[http://dx.doi.org/10.1016/S0140-6736(14)61060-6] [PMID:  25018116] 
[41] 

CNN Philippines Staff TIMELINE. The Dengvaxia controversy., http://cnnphilippines.com/news/2017/12/09/The-Dengvaxia-controversy.html2018
[42] 
 w.h.o. revised sage recommendation on use of dengue vaccine,  http://www.who.int/immunization/diseases/dengue/revised_SAGE_recommendations_dengue_vaccines_ apr2018/en/ (accessed date: 1st june 2018).
[43] 
Behnam, M.A.; Nitsche, C.; Boldescu, V.; Klein, C.D. the medicinal chemistry of dengue virus. J. Med. Chem.,  2016, 59(12), 5622-5649.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01653] [PMID:  26771861] 
[44] 
García, L.L.; Padilla, L.; Castaño, J.C. Inhibitors compounds of the flavivirus replication process. Virol. J.,  2017, 14(1), 95.
[http://dx.doi.org/10.1186/s12985-017-0761-1] [PMID:  28506240] 
[45] 
Lim, S.P.; Noble, C.G.; Shi, P.Y. The dengue virus NS5 protein as a target for drug discovery. Antiviral Res.,  2015, 119, 57-67.
[http://dx.doi.org/10.1016/j.antiviral.2015.04.010] [PMID:  25912817] 
[46] 
Lim, S.P.; Wang, Q.Y.; Noble, C.G.; Chen, Y.L.; Dong, H.; Zou, B.; Yokokawa, F.; Nilar, S.; Smith, P.; Beer, D.; Lescar, J.; Shi, P.Y. Ten years of dengue drug discovery: progress and prospects. Antiviral Res.,  2013, 100(2), 500-519.
[http://dx.doi.org/10.1016/j.antiviral.2013.09.013] [PMID:  24076358] 
[47] 
Noble, C.G.; Chen, Y.L.; Dong, H.; Gu, F.; Lim, S.P.; Schul, W.; Wang, Q.Y.; Shi, P.Y. Strategies for development of Dengue virus inhibitors. Antiviral Res.,  2010, 85(3), 450-462.
[http://dx.doi.org/10.1016/j.antiviral.2009.12.011] [PMID:  20060421] 
[48] 
Noble, C.G.; Shi, P.Y. Structural biology of dengue virus enzymes: towards rational design of therapeutics. Antiviral Res.,  2012, 96(2), 115-126.
[http://dx.doi.org/10.1016/j.antiviral.2012.09.007] [PMID:  22995600] 
[49] 
Wangikar, P.; Martis, E.A.F.; Ambre, P.K.; Nandan, S.; Coutinho, E.C. Update on methyltransferase inhibitors of the dengue virus and further scope in the field. Journal of Infectious Disease and Pathology,  2016, 1(1)
[50] 
Cruz-Oliveira, C.; Freire, J.M.; Conceição, T.M.; Higa, L.M.; Castanho, M.A.; Da Poian, A.T. Receptors and routes of dengue virus entry into the host cells. FEMS Microbiol. Rev.,  2015, 39(2), 155-170.
[http://dx.doi.org/10.1093/femsre/fuu004] [PMID:  25725010] 
[51] 
Ma, L.; Jones, C.T.; Groesch, T.D.; Kuhn, R.J.; Post, C.B. Solution structure of dengue virus capsid protein reveals another fold. Proc. Natl. Acad. Sci. USA,  2004, 101(10), 3414-3419.
[http://dx.doi.org/10.1073/pnas.0305892101] [PMID:  14993605] 
[52] 
Byk, L.A.; Gamarnik, A.V. Properties and functions of the dengue virus capsid protein. Annu. Rev. Virol.,  2016, 3(1), 263-281.
[http://dx.doi.org/10.1146/annurev-virology-110615-042334] [PMID:  27501261] 
[53] 
Klumpp, K.; Crépin, T. Capsid proteins of enveloped viruses as antiviral drug targets. Curr. Opin. Virol.,  2014, 5, 63-71.
[http://dx.doi.org/10.1016/j.coviro.2014.02.002] [PMID:  24607800] 
[54] 
Byrd, C.M.; Dai, D.; Grosenbach, D.W.; Berhanu, A.; Jones, K.F.; Cardwell, K.B.; Schneider, C.; Wineinger, K.A.; Page, J.M.; Harver, C.; Stavale, E.; Tyavanagimatt, S.; Stone, M.A.; Bartenschlager, R.; Scaturro, P.; Hruby, D.E.; Jordan, R. A novel inhibitor of dengue virus replication that targets the capsid protein. Antimicrob. Agents Chemother.,  2013, 57(1), 15-25.
[http://dx.doi.org/10.1128/AAC.01429-12] [PMID:  23070172] 
[55] 
Scaturro, P.; Trist, I.M.; Paul, D.; Kumar, A.; Acosta, E.G.; Byrd, C.M.; Jordan, R.; Brancale, A.; Bartenschlager, R. Characterization of the mode of action of a potent dengue virus capsid inhibitor. J. Virol.,  2014, 88(19), 11540-11555.
[http://dx.doi.org/10.1128/JVI.01745-14] [PMID:  25056895] 
[56] 
Martins, I.C.; Gomes-Neto, F.; Faustino, A.F.; Carvalho, F.A.; Carneiro, F.A.; Bozza, P.T.; Mohana-Borges, R.; Castanho, M.A.; Almeida, F.C.; Santos, N.C.; Da Poian, A.T. The disordered N-terminal region of dengue virus capsid protein contains a lipid-droplet-binding motif. Biochem. J.,  2012, 444(3), 405-415.
[http://dx.doi.org/10.1042/BJ20112219] [PMID:  22428600] 
[57] 
Li, L.; Lok, S-M.; Yu, I-M.; Zhang, Y.; Kuhn, R.J.; Chen, J.; Rossmann, M.G. The flavivirus precursor membrane-envelope protein complex: structure and maturation. Science,  2008, 319(5871), 1830-1834.
[http://dx.doi.org/10.1126/science.1153263] [PMID:  18369147] 
[58] 
Zhang, X.; Ge, P.; Yu, X.; Brannan, J.M.; Bi, G.; Zhang, Q.; Schein, S.; Zhou, Z.H. Cryo-EM structure of the mature dengue virus at 3.5-Å resolution. Nat. Struct. Mol. Biol.,  2013, 20(1), 105-110.
[http://dx.doi.org/10.1038/nsmb.2463] [PMID:  23241927] 
[59] 
Panya, A.; Sawasdee, N.; Junking, M.; Srisawat, C.; Choowongkomon, K.; Yenchitsomanus, P.T. A peptide inhibitor derived from the conserved ectodomain region of DENV membrane (M) protein with activity against dengue virus infection. Chem. Biol. Drug Des.,  2015, 86(5), 1093-1104.
[http://dx.doi.org/10.1111/cbdd.12576] [PMID:  25891143] 
[60] 
Zheng, A.; Umashankar, M.; Kielian, M. In vitro and in vivo studies identify important features of dengue virus pr-E protein interactions. PLoS Pathog.,  2010, 6(10), e1001157.
[http://dx.doi.org/10.1371/journal.ppat.1001157] [PMID:  20975939] 
[61] 
Mukhopadhyay, S.; Kuhn, R.J.; Rossmann, M.G. A structural perspective of the flavivirus life cycle. Nat. Rev. Microbiol.,  2005, 3(1), 13-22.
[http://dx.doi.org/10.1038/nrmicro1067] [PMID:  15608696] 
[62] 
Cambi, A.; de Lange, F.; van Maarseveen, N.M.; Nijhuis, M.; Joosten, B.; van Dijk, E.M.; de Bakker, B.I.; Fransen, J.A.; Bovee-Geurts, P.H.; van Leeuwen, F.N.; Van Hulst, N.F.; Figdor, C.G. Microdomains of the C-type lectin DC-SIGN are portals for virus entry into dendritic cells. J. Cell Biol.,  2004, 164(1), 145-155.
[http://dx.doi.org/10.1083/jcb.200306112] [PMID:  14709546] 
[63] 
Tassaneetrithep, B.; Burgess, T.H.; Granelli-Piperno, A.; Trumpfheller, C.; Finke, J.; Sun, W.; Eller, M.A.; Pattanapanyasat, K.; Sarasombath, S.; Birx, D.L.; Steinman, R.M.; Schlesinger, S.; Marovich, M.A. DC-SIGN (CD209) mediates dengue virus infection of human dendritic cells. J. Exp. Med.,  2003, 197(7), 823-829.
[http://dx.doi.org/10.1084/jem.20021840] [PMID:  12682107] 
[64] 
Dejnirattisai, W.; Wongwiwat, W.; Supasa, S.; Zhang, X.; Dai, X.; Rouvinski, A.; Jumnainsong, A.; Edwards, C.; Quyen, N.T.H.; Duangchinda, T.; Grimes, J.M.; Tsai, W.Y.; Lai, C.Y.; Wang, W.K.; Malasit, P.; Farrar, J.; Simmons, C.P.; Zhou, Z.H.; Rey, F.A.; Mongkolsapaya, J.; Screaton, G.R. A new class of highly potent, broadly neutralizing antibodies isolated from viremic patients infected with dengue virus. Nat. Immunol.,  2015, 16(2), 170-177.
[http://dx.doi.org/10.1038/ni.3058] [PMID:  25501631] 
[65] 
Smith, S.A.; de Alwis, A.R.; Kose, N.; Harris, E.; Ibarra, K.D.; Kahle, K.M.; Pfaff, J.M.; Xiang, X.; Doranz, B.J.; de Silva, A.M.; Austin, S.K.; Sukupolvi-Petty, S.; Diamond, M.S.; Crowe, J.E. Jr. The potent and broadly neutralizing human dengue virus-specific monoclonal antibody 1C19 reveals a unique cross-reactive epitope on the bc loop of domain II of the envelope protein. MBio,  2013, 4(6), e00873-e13.
[http://dx.doi.org/10.1128/mBio.00873-13] [PMID:  24255124] 
[66] 
Alen, M.M.; Schols, D. Dengue virus entry as target for antiviral therapy. J. Trop. Med.,  2012, 2012, 628475.
[http://dx.doi.org/10.1155/2012/628475] [PMID:  22529868] 
[67] 
Sayce, A.C.; Miller, J.L.; Zitzmann, N. Targeting a host process as an antiviral approach against dengue virus. Trends Microbiol.,  2010, 18(7), 323-330.
[http://dx.doi.org/10.1016/j.tim.2010.04.003] [PMID:  20452219] 
[68] 
Yap, S.S.L.; Nguyen-Khuong, T.; Rudd, P.M.; Alonso, S. Dengue virus glycosylation: what do we know? Front. Microbiol.,  2017, 8, 1415.
[http://dx.doi.org/10.3389/fmicb.2017.01415] [PMID:  28791003] 
[69] 
Fibriansah, G.; Ng, T.S.; Kostyuchenko, V.A.; Lee, J.; Lee, S.; Wang, J.; Lok, S.M. Structural changes in dengue virus when exposed to a temperature of 37°C. J. Virol.,  2013, 87(13), 7585-7592.
[http://dx.doi.org/10.1128/JVI.00757-13] [PMID:  23637405] 
[70] 
Yang, J.M.; Chen, Y.F.; Tu, Y.Y.; Yen, K.R.; Yang, Y.L. Combinatorial computational approaches to identify tetracycline derivatives as flavivirus inhibitors. PLoS One,  2007, 2(5), e428.
[http://dx.doi.org/10.1371/journal.pone.0000428] [PMID:  17502914] 
[71] 
Zhou, Z.; Khaliq, M.; Suk, J.E.; Patkar, C.; Li, L.; Kuhn, R.J.; Post, C.B. Antiviral compounds discovered by virtual screening of small-molecule libraries against dengue virus E protein. ACS Chem. Biol.,  2008, 3(12), 765-775.
[http://dx.doi.org/10.1021/cb800176t] [PMID:  19053243] 
[72] 
Li, Z.; Khaliq, M.; Zhou, Z.; Post, C.B.; Kuhn, R.J.; Cushman, M. Design, synthesis, and biological evaluation of antiviral agents targeting flavivirus envelope proteins. J. Med. Chem.,  2008, 51(15), 4660-4671.
[http://dx.doi.org/10.1021/jm800412d] [PMID:  18610998] 
[73] 
Kampmann, T.; Yennamalli, R.; Campbell, P.; Stoermer, M.J.; Fairlie, D.P.; Kobe, B.; Young, P.R. In silico screening of small molecule libraries using the dengue virus envelope E protein has identified compounds with antiviral activity against multiple flaviviruses. Antiviral Res.,  2009, 84(3), 234-241.
[http://dx.doi.org/10.1016/j.antiviral.2009.09.007] [PMID:  19781577] 
[74] 
Yennamalli, R.; Subbarao, N.; Kampmann, T.; McGeary, R.P.; Young, P.R.; Kobe, B. Identification of novel target sites and an inhibitor of the dengue virus E protein. J. Comput. Aided Mol. Des.,  2009, 23(6), 333-341.
[http://dx.doi.org/10.1007/s10822-009-9263-6] [PMID:  19241120] 
[75] 
Wang, Q.Y.; Patel, S.J.; Vangrevelinghe, E.; Xu, H.Y.; Rao, R.; Jaber, D.; Schul, W.; Gu, F.; Heudi, O.; Ma, N.L.; Poh, M.K.; Phong, W.Y.; Keller, T.H.; Jacoby, E.; Vasudevan, S.G. A small-molecule dengue virus entry inhibitor. Antimicrob. Agents Chemother.,  2009, 53(5), 1823-1831.
[http://dx.doi.org/10.1128/AAC.01148-08] [PMID:  19223625] 
[76] 
Poh, M.K.; Yip, A.; Zhang, S.; Priestle, J.P.; Ma, N.L.; Smit, J.M.; Wilschut, J.; Shi, P.Y.; Wenk, M.R.; Schul, W. A small molecule fusion inhibitor of dengue virus. Antiviral Res.,  2009, 84(3), 260-266.
[http://dx.doi.org/10.1016/j.antiviral.2009.09.011] [PMID:  19800368] 
[77] 
Schmidt, A.G.; Lee, K.; Yang, P.L.; Harrison, S.C. Small-molecule inhibitors of dengue-virus entry. PLoS Pathog.,  2012, 8(4), e1002627.
[http://dx.doi.org/10.1371/journal.ppat.1002627] [PMID:  22496653] 
[78] 
Clark, M.J.; Miduturu, C.; Schmidt, A.G.; Zhu, X.; Pitts, J.D.; Wang, J.; Potisopon, S.; Zhang, J.; Wojciechowski, A.; Hann Chu, J.J.; Gray, N.S.; Yang, P.L. gnf-2 inhibits dengue virus by targeting Abl kinases and the viral E protein. Cell Chem. Biol.,  2016, 23(4), 443-452.
[http://dx.doi.org/10.1016/j.chembiol.2016.03.010] [PMID:  27105280] 
[79] 
Abdul Ahmad, S.A.; Palanisamy, U.D.; Tejo, B.A.; Chew, M.F.; Tham, H.W.; Syed Hassan, S. Geraniin extracted from the rind of Nephelium lappaceum binds to dengue virus type-2 envelope protein and inhibits early stage of virus replication. Virol. J.,  2017, 14(1), 229.
[http://dx.doi.org/10.1186/s12985-017-0895-1] [PMID:  29162124] 
[80] 
Kaptein, S.J.; De Burghgraeve, T.; Froeyen, M.; Pastorino, B.; Alen, M.M.; Mondotte, J.A.; Herdewijn, P.; Jacobs, M.; de Lamballerie, X.; Schols, D.; Gamarnik, A.V.; Sztaricskai, F.; Neyts, J. A derivate of the antibiotic doxorubicin is a selective inhibitor of dengue and yellow fever virus replication in vitro. Antimicrob. Agents Chemother.,  2010, 54(12), 5269-5280.
[http://dx.doi.org/10.1128/AAC.00686-10] [PMID:  20837762] 
[81] 
De Burghgraeve, T.; Kaptein, S.J.; Ayala-Nunez, N.V.; Mondotte, J.A.; Pastorino, B.; Printsevskaya, S.S.; de Lamballerie, X.; Jacobs, M.; Preobrazhenskaya, M.; Gamarnik, A.V.; Smit, J.M.; Neyts, J. An analogue of the antibiotic teicoplanin prevents flavivirus entry in vitro. PLoS One,  2012, 7(5), e37244.
[http://dx.doi.org/10.1371/journal.pone.0037244] [PMID:  22624001] 
[82] 
Hrobowski, Y.M.; Garry, R.F.; Michael, S.F. Peptide inhibitors of dengue virus and West Nile virus infectivity. Virol. J.,  2005, 2, 49.
[http://dx.doi.org/10.1186/1743-422X-2-49] [PMID:  15927084] 
[83] 
White, S.H.; Wimley, W.C. Membrane protein folding and stability: physical principles. Annu. Rev. Biophys. Biomol. Struct.,  1999, 28(1), 319-365.
[http://dx.doi.org/10.1146/annurev.biophys.28.1.319] [PMID:  10410805] 
[84] 
Allison, S.L.; Stiasny, K.; Stadler, K.; Mandl, C.W.; Heinz, F.X. Mapping of functional elements in the stem-anchor region of tick-borne encephalitis virus envelope protein E. J. Virol.,  1999, 73(7), 5605-5612.
[http://dx.doi.org/10.1128/JVI.73.7.5605-5612.1999] [PMID:  10364309] 
[85] 
Costin, J.M.; Jenwitheesuk, E.; Lok, S.M.; Hunsperger, E.; Conrads, K.A.; Fontaine, K.A.; Rees, C.R.; Rossmann, M.G.; Isern, S.; Samudrala, R.; Michael, S.F. Structural optimization and de novo design of dengue virus entry inhibitory peptides. PLoS Negl. Trop. Dis.,  2010, 4(6)e721
[http://dx.doi.org/10.1371/journal.pntd.0000721] [PMID:  20582308] 
[86] 
Samudrala, R.; Moult, J. An all-atom distance-dependent conditional probability discriminatory function for protein structure prediction. J. Mol. Biol.,  1998, 275(5), 895-916.
[http://dx.doi.org/10.1006/jmbi.1997.1479] [PMID:  9480776] 
[87] 
Lok, S.M.; Costin, J.M.; Hrobowski, Y.M.; Hoffmann, A.R.; Rowe, D.K.; Kukkaro, P.; Holdaway, H.; Chipman, P.; Fontaine, K.A.; Holbrook, M.R.; Garry, R.F.; Kostyuchenko, V.; Wimley, W.C.; Isern, S.; Rossmann, M.G.; Michael, S.F. Release of dengue virus genome induced by a peptide inhibitor. PLoS One,  2012, 7(11), e50995.
[http://dx.doi.org/10.1371/journal.pone.0050995] [PMID:  23226444] 
[88] 
Nicholson, C.O.; Costin, J.M.; Rowe, D.K.; Lin, L.; Jenwitheesuk, E.; Samudrala, R.; Isern, S.; Michael, S.F. Viral entry inhibitors block dengue antibody-dependent enhancement in vitro. Antiviral Res.,  2011, 89(1), 71-74.
[http://dx.doi.org/10.1016/j.antiviral.2010.11.008] [PMID:  21093488] 
[89] 
Xu, Y.; Rahman, N.A.; Othman, R.; Hu, P.; Huang, M. Computational identification of self-inhibitory peptides from envelope proteins. Proteins,  2012, 80(9), 2154-2168.
[http://dx.doi.org/10.1002/prot.24105] [PMID:  22544824] 
[90] 
Schmidt, A.G.; Yang, P.L.; Harrison, S.C. Peptide inhibitors of dengue-virus entry target a late-stage fusion intermediate. PLoS Pathog.,  2010, 6(4), e1000851.
[http://dx.doi.org/10.1371/journal.ppat.1000851] [PMID:  20386713] 
[91] 
Schmidt, A.G.; Yang, P.L.; Harrison, S.C. Peptide inhibitors of flavivirus entry derived from the E protein stem. J. Virol.,  2010, 84(24), 12549-12554.
[http://dx.doi.org/10.1128/JVI.01440-10] [PMID:  20881042] 
[92] 
Hung, J.J.; Hsieh, M.T.; Young, M.J.; Kao, C.L.; King, C.C.; Chang, W. An external loop region of domain III of dengue virus type 2 envelope protein is involved in serotype-specific binding to mosquito but not mammalian cells. J. Virol.,  2004, 78(1), 378-388.
[http://dx.doi.org/10.1128/JVI.78.1.378-388.2004] [PMID:  14671119] 
[93] 
Mazumder, R.; Hu, Z.Z.; Vinayaka, C.R.; Sagripanti, J.L.; Frost, S.D.; Kosakovsky Pond, S.L.; Wu, C.H. Computational analysis and identification of amino acid sites in dengue E proteins relevant to development of diagnostics and vaccines. Virus Genes,  2007, 35(2), 175-186.
[http://dx.doi.org/10.1007/s11262-007-0103-2] [PMID:  17508277] 
[94] 
Hiramatsu, K.; Tadano, M.; Men, R.; Lai, C.J. Mutational analysis of a neutralization epitope on the dengue type 2 virus (DEN2) envelope protein: monoclonal antibody resistant DEN2/DEN4 chimeras exhibit reduced mouse neurovirulence. Virology,  1996, 224(2), 437-445.
[http://dx.doi.org/10.1006/viro.1996.0550] [PMID:  8874504] 
[95] 
Alhoot, M.A.; Rathinam, A.K.; Wang, S.M.; Manikam, R.; Sekaran, S.D. Inhibition of dengue virus entry into target cells using synthetic antiviral peptides. Int. J. Med. Sci.,  2013, 10(6), 719-729.
[http://dx.doi.org/10.7150/ijms.5037] [PMID:  23630436] 
[96] 
Panya, A.; Bangphoomi, K.; Choowongkomon, K.; Yenchitsomanus, P.T. Peptide inhibitors against dengue virus infection. Chem. Biol. Drug Des.,  2014, 84(2), 148-157.
[http://dx.doi.org/10.1111/cbdd.12309] [PMID:  24612829] 
[97] 
Rentzsch, R.; Renard, B.Y. Docking small peptides remains a great challenge: an assessment using Auto Dock Vina. Brief. Bioinform.,  2015, 16(6), 1045-1056.
[http://dx.doi.org/10.1093/bib/bbv008] [PMID:  25900849] 
[98] 
de la Guardia, C.; Quijada, M.; Lleonart, R. Phage-displayed peptides selected to bind envelope glycoprotein show antiviral activity against dengue virus serotype 2. Adv. Virol.,  2017, 2017, 1827341.
[http://dx.doi.org/10.1155/2017/1827341] [PMID:  29081802] 
[99] 
Chew, M.F.; Tham, H.W.; Rajik, M.; Sharifah, S.H. Anti-dengue virus serotype 2 activity and mode of action of a novel peptide. J. Appl. Microbiol.,  2015, 119(4), 1170-1180.
[http://dx.doi.org/10.1111/jam.12921] [PMID:  26248692] 
[100] 
De Clercq, E.; Li, G. Approved antiviral drugs over the past 50 years. Clin. Microbiol. Rev.,  2016, 29(3), 695-747.
[http://dx.doi.org/10.1128/CMR.00102-15] [PMID:  27281742] 
[101] 
Lalezari, J.P.; Henry, K.; O’Hearn, M.; Montaner, J.S.; Piliero, P.J.; Trottier, B.; Walmsley, S.; Cohen, C.; Kuritzkes, D.R.; Eron, J.J. Jr.; Chung, J.; DeMasi, R.; Donatacci, L.; Drobnes, C.; Delehanty, J.; Salgo, M.; Group, T.S. TORO 1 Study Group. Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America. N. Engl. J. Med.,  2003, 348(22), 2175-2185.
[http://dx.doi.org/10.1056/NEJMoa035026] [PMID:  12637625] 
[102] 
Pugach, P.; Ketas, T.J.; Michael, E.; Moore, J.P. Neutralizing antibody and anti-retroviral drug sensitivities of HIV-1 isolates resistant to small molecule CCR5 inhibitors. Virology,  2008, 377(2), 401-407.
[http://dx.doi.org/10.1016/j.virol.2008.04.032] [PMID:  18519143] 
[103] 
Volz, T.; Allweiss, L. Ben MBarek, M.; Warlich, M.; Lohse, A.W.; Pollok, J.M.; Alexandrov, A.; Urban, S.; Petersen, J.; Lütgehet-mann, M.; Dandri, M. The entry inhibitor Myrcludex-B efficiently blocks intrahepatic virus spreading in humanized mice previously infected with hepatitis B virus. J. Hepatol.,  2013, 58(5), 861-867.
[http://dx.doi.org/10.1016/j.jhep.2012.12.008] [PMID:  23246506] 
[104] 
Lindenbach, B.; Thiel, H. J.; Rice, C. M. flaviviridae: the viruses and their replication, 2007.
[105] 
Edeling, M.A.; Diamond, M.S.; Fremont, D.H. Structural basis of Flavivirus NS1 assembly and antibody recognition. Proc. Natl. Acad. Sci. USA,  2014, 111(11), 4285-4290.
[http://dx.doi.org/10.1073/pnas.1322036111] [PMID:  24594604] 
[106] 
Lindenbach, B.D.; Rice, C.M. trans-Complementation of yellow fever virus NS1 reveals a role in early RNA replication. J. Virol.,  1997, 71(12), 9608-9617.
[http://dx.doi.org/10.1128/JVI.71.12.9608-9617.1997] [PMID:  9371625] 
[107] 
Somnuke, P.; Hauhart, R.E.; Atkinson, J.P.; Diamond, M.S.; Avirutnan, P. N-linked glycosylation of dengue virus NS1 protein modulates secretion, cell-surface expression, hexamer stability, and interactions with human complement. Virology,  2011, 413(2), 253-264.
[http://dx.doi.org/10.1016/j.virol.2011.02.022] [PMID:  21429549] 
[108] 
Muller, D.A.; Young, P.R. The flavivirus NS1 protein: molecular and structural biology, immunology, role in pathogenesis and application as a diagnostic biomarker. Antiviral Res.,  2013, 98(2), 192-208.
[http://dx.doi.org/10.1016/j.antiviral.2013.03.008] [PMID:  23523765] 
[109] 
Winkler, G.; Maxwell, S.E.; Ruemmler, C.; Stollar, V. Newly synthesized dengue-2 virus nonstructural protein NS1 is a soluble protein but becomes partially hydrophobic and membrane-associated after dimerization. Virology,  1989, 171(1), 302-305.
[http://dx.doi.org/10.1016/0042-6822(89)90544-8] [PMID:  2525840] 
[110] 
Flamand, M.; Megret, F.; Mathieu, M.; Lepault, J.; Rey, F.A.; Deubel, V. Dengue virus type 1 nonstructural glycoprotein NS1 is secreted from mammalian cells as a soluble hexamer in a glycosylation-dependent fashion. J. Virol.,  1999, 73(7), 6104-6110.
[http://dx.doi.org/10.1128/JVI.73.7.6104-6110.1999] [PMID:  10364366] 
[111] 
Crabtree, M.B.; Kinney, R.M.; Miller, B.R. Deglycosylation of the NS1 protein of dengue 2 virus, strain 16681: construction and characterization of mutant viruses. Arch. Virol.,  2005, 150(4), 771-786.
[http://dx.doi.org/10.1007/s00705-004-0430-8] [PMID:  15592895] 
[112] 
Pryor, M.J.; Wright, P.J. Glycosylation mutants of dengue virus NS1 protein. J. Gen. Virol.,  1994, 75(Pt 5), 1183-1187.
[http://dx.doi.org/10.1099/0022-1317-75-5-1183] [PMID:  8176380] 
[113] 
Tajima, S.; Takasaki, T.; Kurane, I. Characterization of Asn130-to-Ala mutant of dengue type 1 virus NS1 protein. Virus Genes,  2008, 36(2), 323-329.
[http://dx.doi.org/10.1007/s11262-008-0211-7] [PMID:  18288598] 
[114] 
Lindenbach, B.D.; Rice, C.M. Genetic interaction of flavivirus nonstructural proteins NS1 and NS4A as a determinant of replicase function. J. Virol.,  1999, 73(6), 4611-4621.
[http://dx.doi.org/10.1128/JVI.73.6.4611-4621.1999] [PMID:  10233920] 
[115] 
Youn, S.; Li, T.; McCune, B.T.; Edeling, M.A.; Fremont, D.H.; Cristea, I.M.; Diamond, M.S. Evidence for a genetic and physical interaction between nonstructural proteins NS1 and NS4B that modulates replication of West Nile virus. J. Virol.,  2012, 86(13), 7360-7371.
[http://dx.doi.org/10.1128/JVI.00157-12] [PMID:  22553322] 
[116] 
Avirutnan, P.; Punyadee, N.; Noisakran, S.; Komoltri, C.; Thiemmeca, S.; Auethavornanan, K.; Jairungsri, A.; Kanlaya, R.; Tangthawornchaikul, N.; Puttikhunt, C.; Pattanakitsakul, S.N.; Yenchitsomanus, P.T.; Mongkolsapaya, J.; Kasinrerk, W.; Sittisombut, N.; Husmann, M.; Blettner, M.; Vasanawathana, S.; Bhakdi, S.; Malasit, P. Vascular leakage in severe dengue virus infections: a potential role for the nonstructural viral protein NS1 and complement. J. Infect. Dis.,  2006, 193(8), 1078-1088.
[http://dx.doi.org/10.1086/500949] [PMID:  16544248] 
[117] 
Rathore, A.P.; Paradkar, P.N.; Watanabe, S.; Tan, K.H.; Sung, C.; Connolly, J.E.; Low, J.; Ooi, E.E.; Vasudevan, S.G. Celgosivir treatment misfolds dengue virus NS1 protein, induces cellular pro-survival genes and protects against lethal challenge mouse model. Antiviral Res.,  2011, 92(3), 453-460.
[http://dx.doi.org/10.1016/j.antiviral.2011.10.002] [PMID:  22020302] 
[118] 
Akey, D.L.; Brown, W.C.; Dutta, S.; Konwerski, J.; Jose, J.; Jurkiw, T.J.; DelProposto, J.; Ogata, C.M.; Skiniotis, G.; Kuhn, R.J.; Smith, J.L. Flavivirus NS1 structures reveal surfaces for associations with membranes and the immune system. Science,  2014, 343(6173), 881-885.
[http://dx.doi.org/10.1126/science.1247749] [PMID:  24505133] 
[119] 
Xie, X.; Gayen, S.; Kang, C.; Yuan, Z.; Shi, P.Y. Membrane topology and function of dengue virus NS2A protein. J. Virol.,  2013, 87(8), 4609-4622.
[http://dx.doi.org/10.1128/JVI.02424-12] [PMID:  23408612] 
[120] 
Leung, J.Y.; Pijlman, G.P.; Kondratieva, N.; Hyde, J.; Mackenzie, J.M.; Khromykh, A.A. Role of nonstructural protein NS2A in flavivirus assembly. J. Virol.,  2008, 82(10), 4731-4741.
[http://dx.doi.org/10.1128/JVI.00002-08] [PMID:  18337583] 
[121] 
Muñoz-Jordan, J.L.; Sánchez-Burgos, G.G.; Laurent-Rolle, M.; García-Sastre, A. Inhibition of interferon signaling by dengue virus. Proc. Natl. Acad. Sci. USA,  2003, 100(24), 14333-14338.
[http://dx.doi.org/10.1073/pnas.2335168100] [PMID:  14612562] 
[122] 
Wu, R.H.; Tsai, M.H.; Tsai, K.N.; Tian, J.N.; Wu, J.S.; Wu, S.Y.; Chern, J.H.; Chen, C.H.; Yueh, A. Mutagenesis of dengue virus protein NS2A revealed a novel domain responsible for virus-induced cytopathic effect and interactions between NS2A and NS2B transmembrane segments. J. Virol.,  2017, 91(12), e01836-e16.
[http://dx.doi.org/10.1128/JVI.01836-16] [PMID:  28381578] 
[123] 
Wu, R.H.; Tsai, M.H.; Chao, D.Y.; Yueh, A. Scanning mutagenesis studies reveal a potential intramolecular interaction within the C-terminal half of dengue virus NS2A involved in viral RNA replication and virus assembly and secretion. J. Virol.,  2015, 89(8), 4281-4295.
[http://dx.doi.org/10.1128/JVI.03011-14] [PMID:  25653435] 
[124] 
Li, Y.; Lee, M.Y.; Loh, Y.R.; Kang, C. Secondary structure and membrane topology of dengue virus NS4A protein in micelles. Biochim. Biophys. Acta Biomembr.,  2018, 1860(2), 442-450.
[http://dx.doi.org/10.1016/j.bbamem.2017.10.016] [PMID:  29055659] 
[125] 
Miller, S.; Kastner, S.; Krijnse-Locker, J.; Bühler, S.; Bartenschlager, R. The non-structural protein 4A of dengue virus is an integral membrane protein inducing membrane alterations in a 2K-regulated manner. J. Biol. Chem.,  2007, 282(12), 8873-8882.
[http://dx.doi.org/10.1074/jbc.M609919200] [PMID:  17276984] 
[126] 
Teo, C.S.; Chu, J.J. Cellular vimentin regulates construction of dengue virus replication complexes through interaction with NS4A protein. J. Virol.,  2014, 88(4), 1897-1913.
[http://dx.doi.org/10.1128/JVI.01249-13] [PMID:  24284321] 
[127] 
Lee, C.M.; Xie, X.; Zou, J.; Li, S.H.; Lee, M.Y.; Dong, H.; Qin, C.F.; Kang, C.; Shi, P.Y. Determinants of dengue virus NS4A protein oligomerization. J. Virol.,  2015, 89(12), 6171-6183.
[http://dx.doi.org/10.1128/JVI.00546-15] [PMID:  25833044] 
[128] 
Stern, O.; Hung, Y.F.; Valdau, O.; Yaffe, Y.; Harris, E.; Hoffmann, S.; Willbold, D.; Sklan, E.H. An N-terminal amphipathic helix in dengue virus nonstructural protein 4A mediates oligomerization and is essential for replication. J. Virol.,  2013, 87(7), 4080-4085.
[http://dx.doi.org/10.1128/JVI.01900-12] [PMID:  23325687] 
[129] 
McLean, J.E.; Wudzinska, A.; Datan, E.; Quaglino, D.; Zakeri, Z. Flavivirus NS4A-induced autophagy protects cells against death and enhances virus replication. J. Biol. Chem.,  2011, 286(25), 22147-22159.
[http://dx.doi.org/10.1074/jbc.M110.192500] [PMID:  21511946] 
[130] 
Zou, J.; Xie, X.; Wang, Q.Y.; Dong, H.; Lee, M.Y.; Kang, C.; Yuan, Z.; Shi, P.Y. Characterization of dengue virus NS4A and NS4B protein interaction. J. Virol.,  2015, 89(7), 3455-3470.
[http://dx.doi.org/10.1128/JVI.03453-14] [PMID:  25568208] 
[131] 
Wang, P.; Li, L.F.; Wang, Q.Y.; Shang, L.Q.; Shi, P.Y.; Yin, Z. Anti-dengue-virus activity and structure-activity relationship studies of lycorine derivatives. Chem. Med. Chem,  2014, 9(7), 1522-1533.
[http://dx.doi.org/10.1002/cmdc.201300505] [PMID:  24574246] 
[132] 
Zmurko, J.; Neyts, J.; Dallmeier, K. Flaviviral NS4b, chameleon and jack-in-the-box roles in viral replication and pathogenesis, and a molecular target for antiviral intervention. Rev. Med. Virol.,  2015, 25(4), 205-223.
[http://dx.doi.org/10.1002/rmv.1835] [PMID:  25828437] 
[133] 
Xie, X.; Zou, J.; Wang, Q.Y.; Shi, P.Y. Targeting dengue virus NS4B protein for drug discovery. Antiviral Res.,  2015, 118, 39-45.
[http://dx.doi.org/10.1016/j.antiviral.2015.03.007] [PMID:  25796970] 
[134] 
Miller, S.; Sparacio, S.; Bartenschlager, R. Subcellular localization and membrane topology of the Dengue virus type 2 Non-structural protein 4B. J. Biol. Chem.,  2006, 281(13), 8854-8863.
[http://dx.doi.org/10.1074/jbc.M512697200] [PMID:  16436383] 
[135] 
Zou, J.; Xie, X.; Lee, T.; Chandrasekaran, R.; Reynaud, A.; Yap, L.; Wang, Q.Y.; Dong, H.; Kang, C.; Yuan, Z.; Lescar, J.; Shi, P.Y. Dimerization of flavivirus NS4B protein. J. Virol.,  2014, 88(6), 3379-3391.
[http://dx.doi.org/10.1128/JVI.02782-13] [PMID:  24390334] 
[136] 
Xie, X.; Wang, Q.Y.; Xu, H.Y.; Qing, M.; Kramer, L.; Yuan, Z.; Shi, P.Y. Inhibition of dengue virus by targeting viral NS4B protein. J. Virol.,  2011, 85(21), 11183-11195.
[http://dx.doi.org/10.1128/JVI.05468-11] [PMID:  21865382] 
[137] 
Umareddy, I.; Chao, A.; Sampath, A.; Gu, F.; Vasudevan, S.G. Dengue virus NS4B interacts with NS3 and dissociates it from single-stranded RNA. J. Gen. Virol.,  2006, 87(Pt 9), 2605-2614.
[http://dx.doi.org/10.1099/vir.0.81844-0] [PMID:  16894199] 
[138] 
van Cleef, K.W.; Overheul, G.J.; Thomassen, M.C.; Kaptein, S.J.; Davidson, A.D.; Jacobs, M.; Neyts, J.; van Kuppeveld, F.J.; van Rij, R.P. Identification of a new dengue virus inhibitor that targets the viral NS4B protein and restricts genomic RNA replication. Antiviral Res.,  2013, 99(2), 165-171.
[http://dx.doi.org/10.1016/j.antiviral.2013.05.011] [PMID:  23735301] 
[139] 
Wang, Q.Y.; Dong, H.; Zou, B.; Karuna, R.; Wan, K.F.; Zou, J.; Susila, A.; Yip, A.; Shan, C.; Yeo, K.L.; Xu, H.; Ding, M.; Chan, W.L.; Gu, F.; Seah, P.G.; Liu, W.; Lakshminarayana, S.B.; Kang, C.; Lescar, J.; Blasco, F.; Smith, P.W.; Shi, P.Y. Discovery of Dengue virus NS4B inhibitors. J. Virol.,  2015, 89(16), 8233-8244.
[http://dx.doi.org/10.1128/JVI.00855-15] [PMID:  26018165] 
[140] 
Bianchi, E.; Pessi, A. Inhibiting viral proteases: challenges and opportunities. Biopolymers,  2002, 66(2), 101-114.
[http://dx.doi.org/10.1002/bip.10230] [PMID:  12325160] 
[141] 
Arias, C.F.; Preugschat, F.; Strauss, J.H. Dengue 2 virus NS2B and NS3 form a stable complex that can cleave NS3 within the helicase domain. Virology,  1993, 193(2), 888-899.
[http://dx.doi.org/10.1006/viro.1993.1198] [PMID:  8460492] 
[142] 
Yusof, R.; Clum, S.; Wetzel, M.; Murthy, H.M.K.; Padmanabhan, R. Purified NS2B/NS3 serine protease of dengue virus type 2 exhibits cofactor NS2B dependence for cleavage of substrates with dibasic amino acids in vitro. J. Biol. Chem.,  2000, 275(14), 9963-9969.
[http://dx.doi.org/10.1074/jbc.275.14.9963] [PMID:  10744671] 
[143] 
Nestorowicz, A.; Chambers, T.J.; Rice, C.M. Mutagenesis of the yellow fever virus NS2A/2B cleavage site: effects on proteolytic processing, viral replication, and evidence for alternative processing of the NS2A protein. Virology,  1994, 199(1), 114-123.
[http://dx.doi.org/10.1006/viro.1994.1103] [PMID:  8116234] 
[144] 
Leung, D.; Schroder, K.; White, H.; Fang, N.X.; Stoermer, M.J.; Abbenante, G.; Martin, J.L.; Young, P.R.; Fairlie, D.P. Activity of recombinant dengue 2 virus NS3 protease in the presence of a truncated NS2B co-factor, small peptide substrates, and inhibitors. J. Biol. Chem.,  2001, 276(49), 45762-45771.
[http://dx.doi.org/10.1074/jbc.M107360200] [PMID:  11581268] 
[145] 
Chanprapaph, S.; Saparpakorn, P.; Sangma, C.; Niyomrattanakit, P.; Hannongbua, S.; Angsuthanasombat, C.; Katzenmeier, G. Competitive inhibition of the dengue virus NS3 serine protease by synthetic peptides representing polyprotein cleavage sites. Biochem. Biophys. Res. Commun.,  2005, 330(4), 1237-1246.
[http://dx.doi.org/10.1016/j.bbrc.2005.03.107] [PMID:  15823576] 
[146] 
Yin, Z.; Patel, S.J.; Wang, W.L.; Wang, G.; Chan, W.L.; Rao, K.R.R.; Alam, J.; Jeyaraj, D.A.; Ngew, X.; Patel, V.; Beer, D.; Lim, S.P.; Vasudevan, S.G.; Keller, T.H. Peptide inhibitors of dengue virus NS3 protease. Part 1: Warhead. Bioorg. Med. Chem. Lett.,  2006, 16(1), 36-39.
[http://dx.doi.org/10.1016/j.bmcl.2005.09.062] [PMID:  16246553] 
[147] 
Yin, Z.; Patel, S.J.; Wang, W.L.; Chan, W.L.; Rao, R. K.R.; Wang, G.; Ngew, X.; Patel, V.; Beer, D.; Knox, J.E.; Ma, N.L.; Ehrhardt, C.; Lim, S.P.; Vasudevan, S.G.; Keller, T.H. Peptide inhibitors of dengue virus NS3 protease. Part 2: SAR study of tetrapeptide aldehyde inhibitors. Bioorg. Med. Chem. Lett.,  2006, 16(1), 40-43.
[http://dx.doi.org/10.1016/j.bmcl.2005.09.049] [PMID:  16246563] 
[148] 
Noble, C.G.; Seh, C.C.; Chao, A.T.; Shi, P.Y. Ligand-bound structures of the dengue virus protease reveal the active conformation. J. Virol.,  2012, 86(1), 438-446.
[http://dx.doi.org/10.1128/JVI.06225-11] [PMID:  22031935] 
[149] 
Schüller, A.; Yin, Z.; Brian Chia, C.S.; Doan, D.N.P.; Kim, H.K.; Shang, L.; Loh, T.P.; Hill, J.; Vasudevan, S.G. Tripeptide inhibitors of dengue and West Nile virus NS2B-NS3 protease. Antiviral Res.,  2011, 92(1), 96-101.
[http://dx.doi.org/10.1016/j.antiviral.2011.07.002] [PMID:  21763725] 
[150] 
Nitsche, C.; Behnam, M.A.M.; Steuer, C.; Klein, C.D. Retro peptide-hybrids as selective inhibitors of the Dengue virus NS2B-NS3 protease. Antiviral Res.,  2012, 94(1), 72-79.
[http://dx.doi.org/10.1016/j.antiviral.2012.02.008] [PMID:  22391061] 
[151] 
Nitsche, C.; Schreier, V.N.; Behnam, M.A.M.; Kumar, A.; Bartenschlager, R.; Klein, C.D. Thiazolidinone-peptide hybrids as Dengue virus protease inhibitors with antiviral activity in cell culture. J. Med. Chem.,  2013, 56(21), 8389-8403.
[http://dx.doi.org/10.1021/jm400828u] [PMID:  24083834] 
[152] 
Behnam, M.A.M.; Nitsche, C.; Vechi, S.M.; Klein, C.D. C-terminal residue optimization and fragment merging: discovery of a potent Peptide-hybrid inhibitor of dengue protease. ACS Med. Chem. Lett.,  2014, 5(9), 1037-1042.
[http://dx.doi.org/10.1021/ml500245v] [PMID:  25221663] 
[153] 
Bastos Lima, A.; Behnam, M.A.M.; El Sherif, Y.; Nitsche, C.; Vechi, S.M.; Klein, C.D. Dual inhibitors of the Dengue and West Nile virus NS2B-NS3 proteases: synthesis, biological evaluation and docking studies of novel peptide-hybrids. Bioorg. Med. Chem.,  2015, 23(17), 5748-5755.
[http://dx.doi.org/10.1016/j.bmc.2015.07.012] [PMID:  26233795] 
[154] 
Behnam, M.A.M.; Graf, D.; Bartenschlager, R.; Zlotos, D.P.; Klein, C.D. Discovery of nanomolar Dengue and West Nile virus protease inhibitors containing a 4-benzyloxyphenylglycine residue. J. Med. Chem.,  2015, 58(23), 9354-9370.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01441] [PMID:  26562070] 
[155] 
Weigel, L.F.; Nitsche, C.; Graf, D.; Bartenschlager, R.; Klein, C.D. Phenylalanine and Phenylglycine Analogues as Arginine Mimetics in Dengue Protease Inhibitors. J. Med. Chem.,  2015, 58(19), 7719-7733.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00612] [PMID:  26367391] 
[156] 
Nitsche, C.; Zhang, L.; Weigel, L.F.; Schilz, J.; Graf, D.; Bartenschlager, R.; Hilgenfeld, R.; Klein, C.D. Peptide-boronic acid inhibitors of flaviviral proteases: medicinal chemistry and structural biology. J. Med. Chem.,  2017, 60(1), 511-516.
[http://dx.doi.org/10.1021/acs.jmedchem.6b01021] [PMID:  27966962] 
[157] 
Zhou, G.C.; Weng, Z.; Shao, X.; Liu, F.; Nie, X.; Liu, J.; Wang, D.; Wang, C.; Guo, K. Discovery and SAR studies of methionine-proline anilides as Dengue virus NS2B-NS3 protease inhibitors. Bioorg. Med. Chem. Lett.,  2013, 23(24), 6549-6554.
[http://dx.doi.org/10.1016/j.bmcl.2013.10.071] [PMID:  24268549] 
[158] 
Weng, Z.; Shao, X.; Graf, D.; Wang, C.; Klein, C.D.; Wang, J.; Zhou, G.C. Identification of fused bicyclic derivatives of pyrrolidine and imidazolidinone as dengue virus-2 NS2B-NS3 protease inhibitors. Eur. J. Med. Chem.,  2017, 125, 751-759.
[http://dx.doi.org/10.1016/j.ejmech.2016.09.063] [PMID:  27721158] 
[159] 
Prusis, P.; Lapins, M.; Yahorava, S.; Petrovska, R.; Niyomrattanakit, P.; Katzenmeier, G.; Wikberg, J.E.S. Proteochemometrics analysis of substrate interactions with dengue virus NS3 proteases. Bioorg. Med. Chem.,  2008, 16(20), 9369-9377.
[http://dx.doi.org/10.1016/j.bmc.2008.08.081] [PMID:  18824362] 
[160] 
Prusis, P.; Junaid, M.; Petrovska, R.; Yahorava, S.; Yahorau, A.; Katzenmeier, G.; Lapins, M.; Wikberg, J.E. Design and evaluation of substrate-based octapeptide and non substrate-based tetrapeptide inhibitors of dengue virus NS2B-NS3 proteases. Biochem. Biophys. Res. Commun.,  2013, 434(4), 767-772.
[http://dx.doi.org/10.1016/j.bbrc.2013.03.139] [PMID:  23587903] 
[161] 
Rothan, H.A.; Bahrani, H.; Rahman, N.A.; Yusof, R. Identification of natural antimicrobial agents to treat dengue infection: in vitro analysis of latarcin peptide activity against dengue virus. BMC Microbiol.,  2014, 14, 140.
[http://dx.doi.org/10.1186/1471-2180-14-140] [PMID:  24885331] 
[162] 
Cui, T.A.; Puah, C.M.; Liew, O.W.; Lee, S.H. Novel polypeptides for anti-viral treatment, 2007.
[163] 
Gao, Y.; Cui, T.; Lam, Y. Synthesis and disulfide bond connectivity-activity studies of a kalata B1-inspired cyclopeptide against dengue NS2B-NS3 protease. Bioorg. Med. Chem.,  2010, 18(3), 1331-1336.
[http://dx.doi.org/10.1016/j.bmc.2009.12.026] [PMID:  20042339] 
[164] 
Xu, S.; Li, H.; Shao, X.; Fan, C.; Ericksen, B.; Liu, J.; Chi, C.; Wang, C. Critical effect of peptide cyclization on the potency of peptide inhibitors against Dengue virus NS2B-NS3 protease. J. Med. Chem.,  2012, 55(15), 6881-6887.
[http://dx.doi.org/10.1021/jm300655h] [PMID:  22780881] 
[165] 
Rothan, H.A.; Han, H.C.; Ramasamy, T.S.; Othman, S.; Rahman, N.A.; Yusof, R. Inhibition of dengue NS2B-NS3 protease and viral replication in vero cells by recombinant retrocyclin-1. BMC Infect. Dis.,  2012, 12, 314.
[http://dx.doi.org/10.1186/1471-2334-12-314] [PMID:  23171075] 
[166] 
Rothan, H.A.; Abdulrahman, A.Y.; Sasikumer, P.G.; Othman, S.; Rahman, N.A.; Yusof, R. Protegrin-1 inhibits dengue NS2B-NS3 serine protease and viral replication in MK2 cells. J. Biomed. Biotechnol., 2012., 2012251482
[http://dx.doi.org/10.1155/2012/251482] [PMID:  23093838] 
[167] 
Rothan, H.A.; Mohamed, Z.; Suhaeb, A.M.; Rahman, N.A.; Yusof, R. Antiviral cationic peptides as a strategy for innovation in global health therapeutics for Dengue virus: high yield production of the biologically active recombinant plectasin peptide. OMICS,  2013, 17(11), 560-567.
[http://dx.doi.org/10.1089/omi.2013.0056] [PMID:  24044366] 
[168] 
Rothan, H.A.; Bahrani, H.; Mohamed, Z.; Abd Rahman, N.; Yusof, R. Fusion of protegrin-1 and plectasin to MAP30 shows significant inhibition activity against dengue virus replication. PLoS One,  2014, 9(4), e94561.
[http://dx.doi.org/10.1371/journal.pone.0094561] [PMID:  24722532] 
[169] 
Lin, K.H.; Ali, A.; Rusere, L.; Soumana, D.I.; Kurt Yilmaz, N.; Schiffer, C.A. Dengue virus NS2B/NS3 protease inhibitors exploiting the prime side. J. Virol.,  2017, 91(10), e00045-e17.
[http://dx.doi.org/10.1128/JVI.00045-17] [PMID:  28298600] 
[170] 
Takagi, Y.; Matsui, K.; Nobori, H.; Maeda, H.; Sato, A.; Kurosu, T.; Orba, Y.; Sawa, H.; Hattori, K.; Higashino, K.; Numata, Y.; Yoshida, Y. Discovery of novel cyclic peptide inhibitors of dengue virus NS2B-NS3 protease with antiviral activity. Bioorg. Med. Chem. Lett.,  2017, 27(15), 3586-3590.
[http://dx.doi.org/10.1016/j.bmcl.2017.05.027] [PMID:  28539222] 
[171] 
Bhakat, S.; Delang, L.; Kaptein, S.; Neyts, J.; Leyssen, P.; Jayaprakash, V. Reaching beyond HIV/HCV: nelfinavir as a potential starting point for broad-spectrum protease inhibitors against Dengue and Chikungunya virus. Rsc Adv,  2015, 5(104), 85938-85949.
[http://dx.doi.org/10.1039/C5RA14469H] 
[172] 
Kouretova, J.; Hammamy, M.Z.; Epp, A.; Hardes, K.; Kallis, S.; Zhang, L.; Hilgenfeld, R.; Bartenschlager, R.; Steinmetzer, T. Effects of NS2B-NS3 protease and furin inhibition on West Nile and Dengue virus replication. J. Enzyme Inhib. Med. Chem.,  2017, 32(1), 712-721.
[http://dx.doi.org/10.1080/14756366.2017.1306521] [PMID:  28385094] 
[173] 
Kiat, T.S.; Pippen, R.; Yusof, R.; Ibrahim, H.; Khalid, N.; Rahman, N.A. Inhibitory activity of cyclohexenyl chalcone derivatives and flavonoids of fingerroot, Boesenbergia rotunda (L.), towards dengue-2 virus NS3 protease. Bioorg. Med. Chem. Lett.,  2006, 16(12), 3337-3340.
[http://dx.doi.org/10.1016/j.bmcl.2005.12.075] [PMID:  16621533] 
[174] 
Othman, R.; Kiat, T.S.; Khalid, N.; Yusof, R.; Newhouse, E.I.; Newhouse, J.S.; Alam, M.; Rahman, N.A. Docking of noncompetitive inhibitors into Dengue virus type 2 protease: understanding the interactions with allosteric binding sites. J. Chem. Inf. Model.,  2008, 48(8), 1582-1591.
[http://dx.doi.org/10.1021/ci700388k] [PMID:  18656912] 
[175] 
Heh, C.H.; Othman, R.; Buckle, M.J.C.; Sharifuddin, Y.; Yusof, R.; Rahman, N.A. Rational discovery of dengue type 2 non-competitive inhibitors. Chem. Biol. Drug Des.,  2013, 82(1), 1-11.
[http://dx.doi.org/10.1111/cbdd.12122] [PMID:  23421589] 
[176] 
de Sousa, L.R.F.; Wu, H.; Nebo, L.; Fernandes, J.B.; da Silva, M.F.D.F.; Kiefer, W.; Kanitz, M.; Bodem, J.; Diederich, W.E.; Schirmeister, T.; Vieira, P.C. Flavonoids as noncompetitive inhibitors of Dengue virus NS2B-NS3 protease: inhibition kinetics and docking studies. Bioorg. Med. Chem.,  2015, 23(3), 466-470.
[http://dx.doi.org/10.1016/j.bmc.2014.12.015] [PMID:  25564380] 
[177] 
Shen, X.; Chen, J.; Lee, J.; Mao, F. use of procyanidin in preparation of drugs for treatment of diseases caused by dengue virus infection, china. patent cn105748462a, 2016.
[178] 
Osman, H.; Idris, N.H.; Kamarulzaman, E.E.; Wahab, H.A.; Hassan, M.Z. 3,5-Bis(arylidene)-4-piperidones as potential dengue protease inhibitors. Acta Pharm. Sin. B,  2017, 7(4), 479-484.
[http://dx.doi.org/10.1016/j.apsb.2017.04.009] [PMID:  28752033] 
[179] 
Cregar-Hernandez, L.; Jiao, G-S.; Johnson, A.T.; Lehrer, A.T.; Wong, T.A.S.; Margosiak, S.A. Small molecule pan-dengue and West Nile virus NS3 protease inhibitors. Antivir. Chem. Chemother.,  2011, 21(5), 209-217.
[http://dx.doi.org/10.3851/IMP1767] [PMID:  21566267] 
[180] 
Nitsche, C.; Steuer, C.; Klein, C.D. Arylcyanoacrylamides as inhibitors of the Dengue and West Nile virus proteases. Bioorg. Med. Chem.,  2011, 19(24), 7318-7337.
[http://dx.doi.org/10.1016/j.bmc.2011.10.061] [PMID:  22094280] 
[181] 
Aravapalli, S.; Lai, H.; Teramoto, T.; Alliston, K.R.; Lushington, G.H.; Ferguson, E.L.; Padmanabhan, R.; Groutas, W.C. Inhibitors of Dengue virus and West Nile virus proteases based on the aminobenzamide scaffold. Bioorg. Med. Chem.,  2012, 20(13), 4140-4148.
[http://dx.doi.org/10.1016/j.bmc.2012.04.055] [PMID:  22632792] 
[182] 
Tiew, K.C.; Dou, D.; Teramoto, T.; Lai, H.; Alliston, K.R.; Lushington, G.H.; Padmanabhan, R.; Groutas, W.C. Inhibition of Dengue virus and West Nile virus proteases by click chemistry-derived benz[d]isothiazol-3(2H)-one derivatives. Bioorg. Med. Chem.,  2012, 20(3), 1213-1221.
[http://dx.doi.org/10.1016/j.bmc.2011.12.047] [PMID:  22249124] 
[183] 
Irwin, J.J.; Shoichet, B.K. ZINC--a free database of commercially available compounds for virtual screening. J. Chem. Inf. Model.,  2005, 45(1), 177-182.
[http://dx.doi.org/10.1021/ci049714+] [PMID:  15667143] 
[184] 
Lai, H.; Sridhar Prasad, G.; Padmanabhan, R. Characterization of 8-hydroxyquinoline derivatives containing aminobenzothiazole as inhibitors of dengue virus type 2 protease in vitro. Antiviral Res.,  2013, 97(1), 74-80.
[http://dx.doi.org/10.1016/j.antiviral.2012.10.009] [PMID:  23127365] 
[185] 
Lai, H.; Dou, D.; Aravapalli, S.; Teramoto, T.; Lushington, G.H.; Mwania, T.M.; Alliston, K.R.; Eichhorn, D.M.; Padmanabhan, R.; Groutas, W.C. Design, synthesis and characterization of novel 1,2-benzisothiazol-3(2H)-one and 1,3,4-oxadiazole hybrid derivatives: potent inhibitors of Dengue and West Nile virus NS2B/NS3 proteases. Bioorg. Med. Chem.,  2013, 21(1), 102-113.
[http://dx.doi.org/10.1016/j.bmc.2012.10.058] [PMID:  23211969] 
[186] 
Liu, H.; Wu, R.; Sun, Y.; Ye, Y.; Chen, J.; Luo, X.; Shen, X.; Liu, H. Identification of novel thiadiazoloacrylamide analogues as inhibitors of dengue-2 virus NS2B/NS3 protease. Bioorg. Med. Chem.,  2014, 22(22), 6344-6352.
[http://dx.doi.org/10.1016/j.bmc.2014.09.057] [PMID:  25438757] 
[187] 
Padmanabhan, R.; Nagarajan, K.; Rao, K. S.; Shridhara, K. shashiprabha; harisha, a. s., dengue and west nile virus protease inhibitors. pct int. appl., 2014, wo 2014164667 a1 20141009. 
[188] 
Timiri, A.K.; Selvarasu, S.; Kesherwani, M.; Vijayan, V.; Sinha, B.N.; Devadasan, V.; Jayaprakash, V. Synthesis and molecular modelling studies of novel sulphonamide derivatives as dengue virus 2 protease inhibitors. Bioorg. Chem.,  2015, 62, 74-82.
[http://dx.doi.org/10.1016/j.bioorg.2015.07.005] [PMID:  26247308] 
[189] 
Wu, H.; Bock, S.; Snitko, M.; Berger, T.; Weidner, T.; Holloway, S.; Kanitz, M.; Diederich, W.E.; Steuber, H.; Walter, C.; Hofmann, D.; Weißbrich, B.; Spannaus, R.; Acosta, E.G.; Bartenschlager, R.; Engels, B.; Schirmeister, T.; Bodem, J. Novel dengue virus NS2B/NS3 protease inhibitors. Antimicrob. Agents Chemother.,  2015, 59(2), 1100-1109.
[http://dx.doi.org/10.1128/AAC.03543-14] [PMID:  25487800] 
[190] 
Pelliccia, S.; Wu, Y.H.; Coluccia, A.; La Regina, G.; Tseng, C.K.; Famiglini, V.; Masci, D.; Hiscott, J.; Lee, J.C.; Silvestri, R. Inhibition of Dengue virus replication by novel inhibitors of RNA-dependent RNA polymerase and protease activities. J. Enzyme Inhib. Med. Chem.,  2017, 32(1), 1091-1101.
[http://dx.doi.org/10.1080/14756366.2017.1355791] [PMID:  28776445] 
[191] 
Rothan, H.A.; Buckle, M.J.; Ammar, Y.A.; Mohammadjavad, P.; Shatrah, O.; Noorsaadah, A.R.; Rohana, Y. Study the antiviral activity of some derivatives of tetracycline and non-steroid anti-inflammatory drugs towards Dengue virus. Trop. Biomed.,  2013, 30(4), 681-690.
[PMID:  24522138] 
[192] 
Wu, D.W.; Mao, F.; Ye, Y.; Li, J.; Xu, C.L.; Luo, X.M.; Chen, J.; Shen, X. Policresulen, a novel NS2B/NS3 protease inhibitor, effectively inhibits the replication of DENV2 virus in BHK-21 cells. Acta Pharmacol. Sin.,  2015, 36(9), 1126-1136.
[http://dx.doi.org/10.1038/aps.2015.56] [PMID:  26279156] 
[193] 
Li, Z.; Sakamuru, S.; Huang, R.; Brecher, M.; Koetzner, C.A.; Zhang, J.; Chen, H.; Qin, C.F.; Zhang, Q.-Y.; Zhou, J.; Kramer, L.D.; Xia, M.; Li, H. Erythrosin B is a potent and broad-spectrum orthosteric inhibitor of the flavivirus NS2B-NS3 protease. Antiviral Res.,  2018, 150, 217-225.
[http://dx.doi.org/10.1016/j.antiviral.2017.12.018] [PMID:  29288700] 
[194] 
Yang, C.C.; Hsieh, Y.C.; Lee, S.J.; Wu, S.H.; Liao, C.L.; Tsao, C.H.; Chao, Y.S.; Chern, J.H.; Wu, C.P.; Yueh, A. Novel dengue virus-specific NS2B/NS3 protease inhibitor, BP2109, discovered by a high-throughput screening assay. Antimicrob. Agents Chemother.,  2011, 55(1), 229-238.
[http://dx.doi.org/10.1128/AAC.00855-10] [PMID:  20937790] 
[195] 
Balasubramanian, A.; Manzano, M.; Teramoto, T.; Pilankatta, R.; Padmanabhan, R. High-throughput screening for the identification of small-molecule inhibitors of the flaviviral protease. Antiviral Res.,  2016, 134, 6-16.
[http://dx.doi.org/10.1016/j.antiviral.2016.08.014] [PMID:  27539384] 
[196] 
Tomlinson, S.M.; Malmstrom, R.D.; Russo, A.; Mueller, N.; Pang, Y-P.; Watowich, S.J. Structure-based discovery of dengue virus protease inhibitors. Antiviral Res.,  2009, 82(3), 110-114.
[http://dx.doi.org/10.1016/j.antiviral.2009.02.190] [PMID:  19428601] 
[197] 
Tomlinson, S.M.; Watowich, S.J. Anthracene-based inhibitors of dengue virus NS2B-NS3 protease. Antiviral Res.,  2011, 89(2), 127-135.
[http://dx.doi.org/10.1016/j.antiviral.2010.12.006] [PMID:  21185332] 
[198] 
Watowich, S.J.; Tomlinson, S.M.; Gilbertson, S. smallmolecule inhibitors of dengue and west nile virus proteases. u.s. pat. appl. publ., us 20130035284 a1 20130207, 2013.
[199] 
Watowich, S.J.; Viswanathan, U. small-molecule inhibitors of dengue virus proteases. u.s. pat. appl. publ., us 20150141521 a1 20150521, 2015.
[200] 
Viswanathan, U.; Tomlinson, S.M.; Fonner, J.M.; Mock, S.A.; Watowich, S.J. Identification of a novel inhibitor of dengue virus protease through use of a virtual screening drug discovery Web portal. J. Chem. Inf. Model.,  2014, 54(10), 2816-2825.
[http://dx.doi.org/10.1021/ci500531r] [PMID:  25263519] 
[201] 
Tomlinson, S.M.; Watowich, S.J. Use of parallel validation high-throughput screens to reduce false positives and identify novel dengue NS2B-NS3 protease inhibitors. Antiviral Res.,  2012, 93(2), 245-252.
[http://dx.doi.org/10.1016/j.antiviral.2011.12.003] [PMID:  22193283] 
[202] 
Deng, J.; Li, N.; Liu, H.; Zuo, Z.; Liew, O.W.; Xu, W.; Chen, G.; Tong, X.; Tang, W.; Zhu, J.; Zuo, J.; Jiang, H.; Yang, C.G.; Li, J.; Zhu, W. Discovery of novel small molecule inhibitors of dengue viral NS2B-NS3 protease using virtual screening and scaffold hopping. J. Med. Chem.,  2012, 55(14), 6278-6293.
[http://dx.doi.org/10.1021/jm300146f] [PMID:  22742496] 
[203] 
Pambudi, S.; Kawashita, N.; Phanthanawiboon, S.; Omokoko, M.D.; Masrinoul, P.; Yamashita, A.; Limkittikul, K.; Yasunaga, T.; Takagi, T.; Ikuta, K.; Kurosu, T. A small compound targeting the interaction between nonstructural proteins 2B and 3 inhibits dengue virus replication. Biochem. Biophys. Res. Commun.,  2013, 440(3), 393-398.
[http://dx.doi.org/10.1016/j.bbrc.2013.09.078] [PMID:  24070610] 
[204] 
Nguyen, T.T.H.; Lee, S.; Wang, H.K.; Chen, H.Y.; Wu, Y.T.; Lin, S.C.; Kim, D.W.; Kim, D. In vitro evaluation of novel inhibitors against the NS2B-NS3 protease of dengue fever virus type 4. Molecules,  2013, 18(12), 15600-15612.
[http://dx.doi.org/10.3390/molecules181215600] [PMID:  24352016] 
[205] 
Mukhametov, A.; Newhouse, E.I.; Aziz, N.A.; Saito, J.A.; Alam, M. Allosteric pocket of the dengue virus (serotype 2) NS2B/NS3 protease: in silico ligand screening and molecular dynamics studies of inhibition. J. Mol. Graph. Model.,  2014, 52, 103-113.
[http://dx.doi.org/10.1016/j.jmgm.2014.06.008] [PMID:  25023665] 
[206] 
Raut, R.; Beesetti, H.; Tyagi, P.; Khanna, I.; Jain, S.K.; Jeankumar, V.U.; Yogeeswari, P.; Sriram, D.; Swaminathan, S. A small molecule inhibitor of dengue virus type 2 protease inhibits the replication of all four dengue virus serotypes in cell culture. Virol. J.,  2015, 12, 16.
[http://dx.doi.org/10.1186/s12985-015-0248-x] [PMID:  25886260] 
[207] 
Cabarcas-Montalvo, M.; Maldonado-Rojas, W.; Montes-Grajales, D.; Bertel-Sevilla, A.; Wagner-Döbler, I.; Sztajer, H.; Reck, M.; Flechas-Alarcon, M.; Ocazionez, R.; Olivero-Verbel, J. Discovery of antiviral molecules for dengue: in silico search and biological evaluation. Eur. J. Med. Chem.,  2016, 110, 87-97.
[http://dx.doi.org/10.1016/j.ejmech.2015.12.030] [PMID:  26807547] 
[208] 
Brecher, M.; Li, Z.; Liu, B.; Zhang, J.; Koetzner, C.A.; Alifarag, A.; Jones, S.A.; Lin, Q.; Kramer, L.D.; Li, H. A conformational switch high-throughput screening assay and allosteric inhibition of the flavivirus NS2B-NS3 protease. PLoS Pathog.,  2017, 13(5), e1006411.
[http://dx.doi.org/10.1371/journal.ppat.1006411] [PMID:  28542603] 
[209] 
Mirza, S.B.; Lee, R.C.H.; Chu, J.J.H.; Salmas, R.E.; Mavromoustakos, T.; Durdagi, S. Discovery of selective dengue virus inhibitors using combination of molecular fingerprint-based virtual screening protocols, structure-based pharmacophore model development, molecular dynamics simulations and in vitro studies. J. Mol. Graph. Model.,  2017, 77, 338-355.
[PMID:  28957754] 
[210] 
Knehans, T.; Schüller, A.; Doan, D.N.; Nacro, K.; Hill, J.; Güntert, P.; Madhusudhan, M.S.; Weil, T.; Vasudevan, S.G. Structure-guided fragment-based in silico drug design of dengue protease inhibitors. J. Comput. Aided Mol. Des.,  2011, 25(3), 263-274.
[http://dx.doi.org/10.1007/s10822-011-9418-0] [PMID:  21344277] 
[211] 
Steuer, C.; Gege, C.; Fischl, W.; Heinonen, K.H.; Bartenschlager, R.; Klein, C.D. Synthesis and biological evaluation of α-ketoamides as inhibitors of the Dengue virus protease with antiviral activity in cell-culture. Bioorg. Med. Chem.,  2011, 19(13), 4067-4074.
[http://dx.doi.org/10.1016/j.bmc.2011.05.015] [PMID:  21641807] 
[212] 
Li, L.; Basavannacharya, C.; Chan, K.W.K.; Shang, L.; Vasudevan, S.G.; Yin, Z. Structure-guided discovery of a novel non-peptide inhibitor of Dengue virus NS2B-NS3 protease. Chem. Biol. Drug Des.,  2015, 86(3), 255-264.
[http://dx.doi.org/10.1111/cbdd.12500] [PMID:  25533891] 
[213] 
Chiang, P.Y.; Wu, H.N. The role of surface basic amino acids of dengue virus NS3 helicase in viral RNA replication and enzyme activities. FEBS Lett.,  2016, 590(14), 2307-2320.
[http://dx.doi.org/10.1002/1873-3468.12232] [PMID:  27273003] 
[214] 
Luo, D.; Xu, T.; Hunke, C.; Grüber, G.; Vasudevan, S.G.; Lescar, J. Crystal structure of the NS3 protease-helicase from Dengue virus. J. Virol.,  2008, 82(1), 173-183.
[http://dx.doi.org/10.1128/JVI.01788-07] [PMID:  17942558] 
[215] 
Sampath, A.; Xu, T.; Chao, A.; Luo, D.; Lescar, J.; Vasudevan, S.G. Structure-based mutational analysis of the NS3 helicase from Dengue virus. J. Virol.,  2006, 80(13), 6686-6690.
[http://dx.doi.org/10.1128/JVI.02215-05] [PMID:  16775356] 
[216] 
Swarbrick, C.M.D.; Basavannacharya, C.; Chan, K.W.K.; Chan, S.A.; Singh, D.; Wei, N.; Phoo, W.W.; Luo, D.; Lescar, J.; Vasudevan, S.G. NS3 helicase from Dengue virus specifically recognizes viral RNA sequence to ensure optimal replication. Nucleic Acids Res.,  2017, 45(22), 12904-12920.
[http://dx.doi.org/10.1093/nar/gkx1127] [PMID:  29165589] 
[217] 
Luo, D.; Xu, T.; Watson, R.P.; Scherer-Becker, D.; Sampath, A.; Jahnke, W.; Yeong, S.S.; Wang, C.H.; Lim, S.P.; Strongin, A.; Vasudevan, S.G.; Lescar, J. Insights into RNA unwinding and ATP hydrolysis by the flavivirus NS3 protein. EMBO J.,  2008, 27(23), 3209-3219.
[http://dx.doi.org/10.1038/emboj.2008.232] [PMID:  19008861] 
[218] 
Borowski, P.; Niebuhr, A.; Schmitz, H.; Hosmane, R.S.; Bretner, M.; Siwecka, M.A.; Kulikowski, T. NTPase/helicase of Flaviviridae: inhibitors and inhibition of the enzyme. Acta Biochim. Pol.,  2002, 49(3), 597-614.
[http://dx.doi.org/10.18388/abp.2002_3769] [PMID:  12422230] 
[219] 
da Costa, E.C.; Amorim, R.; da Silva, F.C.; Rocha, D.R.; Papa, M.P.; de Arruda, L.B.; Mohana-Borges, R.; Ferreira, V.F.; Tanuri, A.; da Costa, L.J.; Ferreira, S.B. Synthetic 1,4-pyran naphthoquinones are potent inhibitors of Dengue virus replication. PLoS One,  2013, 8(12), e82504.
[http://dx.doi.org/10.1371/journal.pone.0082504] [PMID:  24376541] 
[220] 
Sweeney, N.L.; Hanson, A.M.; Mukherjee, S.; Ndjomou, J.; Geiss, B.J.; Steel, J.J.; Frankowski, K.J.; Li, K.; Schoenen, F.J.; Frick, D.N. Benzothiazole and pyrrolone Flavivirus inhibitors targeting the viral helicase. ACS Infect. Dis.,  2015, 1(3), 140-148.
[http://dx.doi.org/10.1021/id5000458] [PMID:  26029739] 
[221] 
Pan, A.; Saw, W.G.; Subramanian Manimekalai, M.S.; Grüber, A.; Joon, S.; Matsui, T.; Weiss, T.M.; Grüber, G. Structural features of NS3 of Dengue virus serotypes 2 and 4 in solution and insight into RNA binding and the inhibitory role of quercetin. Acta Crystallogr. D Struct. Biol.,  2017, 73(Pt 5), 402-419.
[http://dx.doi.org/10.1107/S2059798317003849] [PMID:  28471365] 
[222] 
Byrd, C.M.; Grosenbach, D.W.; Berhanu, A.; Dai, D.; Jones, K.F.; Cardwell, K.B.; Schneider, C.; Yang, G.; Tyavanagimatt, S.; Harver, C.; Wineinger, K.A.; Page, J.; Stavale, E.; Stone, M.A.; Fuller, K.P.; Lovejoy, C.; Leeds, J.M.; Hruby, D.E.; Jordan, R. Novel benzoxazole inhibitor of dengue virus replication that targets the NS3 helicase. Antimicrob. Agents Chemother.,  2013, 57(4), 1902-1912.
[http://dx.doi.org/10.1128/AAC.02251-12] [PMID:  23403421] 
[223] 
Basavannacharya, C.; Vasudevan, S.G. Suramin inhibits helicase activity of NS3 protein of Dengue virus in a fluorescence-based high throughput assay format. Biochem. Biophys. Res. Commun.,  2014, 453(3), 539-544.
[http://dx.doi.org/10.1016/j.bbrc.2014.09.113] [PMID:  25281902] 
[224] 
Mastrangelo, E.; Pezzullo, M.; De Burghgraeve, T.; Kaptein, S.; Pastorino, B.; Dallmeier, K.; de Lamballerie, X.; Neyts, J.; Hanson, A.M.; Frick, D.N.; Bolognesi, M.; Milani, M. Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: new prospects for an old drug. J. Antimicrob. Chemother.,  2012, 67(8), 1884-1894.
[http://dx.doi.org/10.1093/jac/dks147] [PMID:  22535622] 
[225] 
El Sahili, A.; Lescar, J. Dengue virus non-structural protein 5. Viruses,  2017, 9(4), E91.
[http://dx.doi.org/10.3390/v9040091] [PMID:  28441781] 
[226] 
Potisopon, S.; Priet, S.; Collet, A.; Decroly, E.; Canard, B.; Selisko, B. The methyltransferase domain of dengue virus protein NS5 ensures efficient RNA synthesis initiation and elongation by the polymerase domain. Nucleic Acids Res.,  2016, 44(6), 2974.
[http://dx.doi.org/10.1093/nar/gkv1294] [PMID:  26578566] 
[227] 
Klema, V.J.; Ye, M.; Hindupur, A.; Teramoto, T.; Gottipati, K.; Padmanabhan, R.; Choi, K.H. Dengue Virus Nonstructural Protein 5 (NS5) Assembles into a Dimer with a Unique Methyltransferase and Polymerase Interface. PLoS Pathog.,  2016, 12(2)e1005451
[http://dx.doi.org/10.1371/journal.ppat.1005451] [PMID:  26895240] 
[228] 
Dong, H.; Fink, K.; Züst, R.; Lim, S.P.; Qin, C.F.; Shi, P.Y. Flavivirus RNA methylation. J. Gen. Virol.,  2014, 95(Pt 4), 763-778.
[http://dx.doi.org/10.1099/vir.0.062208-0] [PMID:  24486628] 
[229] 
Zhou, Y.; Ray, D.; Zhao, Y.; Dong, H.; Ren, S.; Li, Z.; Guo, Y.; Bernard, K.A.; Shi, P.Y.; Li, H. Structure and function of flavivirus NS5 methyltransferase. J. Virol.,  2007, 81(8), 3891-3903.
[http://dx.doi.org/10.1128/JVI.02704-06] [PMID:  17267492] 
[230] 
Dong, H.; Liu, L.; Zou, G.; Zhao, Y.; Li, Z.; Lim, S.P.; Shi, P.Y.; Li, H. Structural and functional analyses of a conserved hydrophobic pocket of flavivirus methyltransferase. J. Biol. Chem.,  2010, 285(42), 32586-32595.
[http://dx.doi.org/10.1074/jbc.M110.129197] [PMID:  20685660] 
[231] 
Lim, S.P.; Sonntag, L.S.; Noble, C.; Nilar, S.H.; Ng, R.H.; Zou, G.; Monaghan, P.; Chung, K.Y.; Dong, H.; Liu, B.; Bodenreider, C.; Lee, G.; Ding, M.; Chan, W.L.; Wang, G.; Jian, Y.L.; Chao, A.T.; Lescar, J.; Yin, Z.; Vedananda, T.R.; Keller, T.H.; Shi, P.Y. Small molecule inhibitors that selectively block dengue virus methyltransferase. J. Biol. Chem.,  2011, 286(8), 6233-6240.
[http://dx.doi.org/10.1074/jbc.M110.179184] [PMID:  21147775] 
[232] 
Egloff, M.P.; Decroly, E.; Malet, H.; Selisko, B.; Benarroch, D.; Ferron, F.; Canard, B. Structural and functional analysis of methylation and 5′-RNA sequence requirements of short capped RNAs by the methyltransferase domain of dengue virus NS5. J. Mol. Biol.,  2007, 372(3), 723-736.
[http://dx.doi.org/10.1016/j.jmb.2007.07.005] [PMID:  17686489] 
[233] 
Henderson, B.R.; Saeedi, B.J.; Campagnola, G.; Geiss, B.J. Analysis of RNA binding by the dengue virus NS5 RNA capping enzyme. PLoS One,  2011, 6(10), e25795.
[http://dx.doi.org/10.1371/journal.pone.0025795] [PMID:  22022449] 
[234] 
Chung, K.Y.; Dong, H.; Chao, A.T.; Shi, P.Y.; Lescar, J.; Lim, S.P. Higher catalytic efficiency of N-7-methylation is responsible for processive N-7 and 2′-O methyltransferase activity in dengue virus. Virology,  2010, 402(1), 52-60.
[http://dx.doi.org/10.1016/j.virol.2010.03.011] [PMID:  20350738] 
[235] 
Noble, C.G.; Li, S.H.; Dong, H.; Chew, S.H.; Shi, P.Y. Crystal structure of Dengue virus methyltransferase without S-adenosyl-L-methionine. Antiviral Res.,  2014, 111, 78-81.
[http://dx.doi.org/10.1016/j.antiviral.2014.09.003] [PMID:  25241250] 
[236] 
Zweygarth, E.; Schillinger, D.; Kaufmann, W.; Rottcher, D.  evaluation of sinefungin for the treatment of trypanosoma (nannomonas) congolense infections in goats. tropical medicine and parasitology : official organ of deutsche tropenmedizinische gesellschaft and of deutsche gesellschaft fur technische zusammenarbeit, 1986, 37(3), 255-257.
[237] 
Trott, O.; Olson, A.J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem.,  2010, 31(2), 455-461.
[http://dx.doi.org/10.1002/jcc.21334]] [PMID:  19499576] 
[238] 
Brecher, M.; Chen, H.; Li, Z.; Banavali, N.K.; Jones, S.A.; Zhang, J.; Kramer, L.D.; Li, H. Identification and characterization of novel broad-spectrum inhibitors of the Flavivirus methyltransferase. ACS Infect. Dis.,  2015, 1(8), 340-349.
[http://dx.doi.org/10.1021/acsinfecdis.5b00070] [PMID:  26726314] 
[239] 
Brecher, M.; Chen, H.; Liu, B.; Banavali, N.K.; Jones, S.A.; Zhang, J.; Li, Z.; Kramer, L.D.; Li, H. Novel broad spectrum inhibitors targeting the Flavivirus methyltransferase. PLoS One,  2015, 10(6), e0130062.
[http://dx.doi.org/10.1371/journal.pone.0130062] [PMID:  26098995] 
[240] 
Vernekar, S.K.; Qiu, L.; Zhang, J.; Kankanala, J.; Li, H.; Geraghty, R.J.; Wang, Z. 5′-Silylated 3′-1,2,3-triazolyl thymidine analogues as inhibitors of West Nile virus and Dengue virus. J. Med. Chem.,  2015, 58(9), 4016-4028.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00327] [PMID:  25909386] 
[241] 
Verdonk, M.L.; Cole, J.C.; Hartshorn, M.J.; Murray, C.W.; Taylor, R.D. Improved protein-ligand docking using GOLD. Proteins,  2003, 52(4), 609-623.
[http://dx.doi.org/10.1002/prot.10465] [PMID:  12910460] 
[242] 
Luzhkov, V.B.; Selisko, B.; Nordqvist, A.; Peyrane, F.; Decroly, E.; Alvarez, K.; Karlen, A.; Canard, B.; Qvist, J. Virtual screening and bioassay study of novel inhibitors for dengue virus mRNA cap (nucleoside-2'O)-methyltrans-ferase. Bioorg. Med. Chem.,  2007, 15(24), 7795-7802.
[http://dx.doi.org/10.1016/j.bmc.2007.08.049] [PMID:  17888664] 
[243] 
Friesner, R.A.; Banks, J.L.; Murphy, R.B.; Halgren, T.A.; Klicic, J.J.; Mainz, D.T.; Repasky, M.P.; Knoll, E.H.; Shelley, M.; Perry, J.K.; Shaw, D.E.; Francis, P.; Shenkin, P.S. Glide: a new approach for rapid, accurate docking and scoring. Method and assessment of docking accuracy. J. Med. Chem.,  2004, 47(7), 1739-1749.
[http://dx.doi.org/10.1021/jm0306430] [PMID:  15027865] 
[244] 
Halgren, T.A.; Murphy, R.B.; Friesner, R.A.; Beard, H.S.; Frye, L.L.; Pollard, W.T.; Banks, J.L. Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J. Med. Chem.,  2004, 47(7), 1750-1759.
[http://dx.doi.org/10.1021/jm030644s] [PMID:  15027866] 
[245] 
Podvinec, M.; Lim, S.P.; Schmidt, T.; Scarsi, M.; Wen, D.; Sonntag, L.S.; Sanschagrin, P.; Shenkin, P.S.; Schwede, T. Novel inhibitors of dengue virus methyltransferase: discovery by in vitro-driven virtual screening on a desktop computer grid. J. Med. Chem.,  2010, 53(4), 1483-1495.
[http://dx.doi.org/10.1021/jm900776m] [PMID:  20108931] 
[246] 
Lim, S.P.; Wen, D.; Yap, T.L.; Yan, C.K.; Lescar, J.; Vasudevan, S.G. A scintillation proximity assay for Dengue virus NS5 2′-O-methyltransferase-kinetic and inhibition analyses. Antiviral Res.,  2008, 80(3), 360-369.
[http://dx.doi.org/10.1016/j.antiviral.2008.08.005] [PMID:  18809436] 
[247] 
Benarroch, D.; Egloff, M.P.; Mulard, L.; Guerreiro, C.; Romette, J.L.; Canard, B. A structural basis for the inhibition of the NS5 dengue virus mRNA 2′-O-methyltransferase domain by ribavirin 5′-triphosphate. J. Biol. Chem.,  2004, 279(34), 35638-35643.
[http://dx.doi.org/10.1074/jbc.M400460200] [PMID:  15152003] 
[248] 
Fusco, D.N.; Chung, R.T. Review of current Dengue treatment and therapeutics in development. J. Bioanal. Biomed.,  2014, S8(002).
[http://dx.doi.org/10.4172/1948-593X.S8-002] 
[249] 
Malinoski, F.J.; Hasty, S.E.; Ussery, M.A.; Dalrymple, J.M. Prophylactic ribavirin treatment of dengue type 1 infection in Rhesus monkeys. Antiviral Res.,  1990, 13(3), 139-149.
[http://dx.doi.org/10.1016/0166-3542(90)90029-7] [PMID:  2353804] 
[250] 
Schul, W.; Liu, W.; Xu, H.Y.; Flamand, M.; Vasudevan, S.G. A dengue fever viremia model in mice shows reduction in viral replication and suppression of the inflammatory response after treatment with antiviral drugs. J. Infect. Dis.,  2007, 195(5), 665-674.
[http://dx.doi.org/10.1086/511310] [PMID:  17262707] 
[251] 
Chang, J.; Schul, W.; Butters, T.D.; Yip, A.; Liu, B.; Goh, A.; Lakshminarayana, S.B.; Alonzi, D.; Reinkensmeier, G.; Pan, X.; Qu, X.; Weidner, J.M.; Wang, L.; Yu, W.; Borune, N.; Kinch, M.A.; Rayahin, J.E.; Moriarty, R.; Xu, X.; Shi, P.Y.; Guo, J.T.; Block, T.M. Combination of α-glucosidase inhibitor and ribavirin for the treatment of dengue virus infection in vitro and in vivo. Antiviral Res.,  2011, 89(1), 26-34.
[http://dx.doi.org/10.1016/j.antiviral.2010.11.002] [PMID:  21073903] 
[252] 
Stahla-Beek, H.J.; April, D.G.; Saeedi, B.J.; Hannah, A.M.; Keenan, S.M.; Geiss, B.J. Identification of a novel antiviral inhibitor of the Flavivirus guanylyltransferase enzyme. J. Virol.,  2012, 86(16), 8730-8739.
[http://dx.doi.org/10.1128/JVI.00384-12] [PMID:  22674988] 
[253] 
Bullard, K.M.; Gullberg, R.C.; Soltani, E.; Steel, J.J.; Geiss, B.J.; Keenan, S.M. Murine efficacy and pharmacokinetic evaluation of the Flaviviral NS5 capping enzyme 2-thioxothiazolidin-4-one inhibitor BG-323. PLoS One,  2015, 10(6), e0130083.
[http://dx.doi.org/10.1371/journal.pone.0130083] [PMID:  26075394] 
[254] 
Morris, G.M.; Huey, R.; Lindstrom, W.; Sanner, M.F.; Belew, R.K.; Goodsell, D.S.; Olson, A.J. AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J. Comput. Chem.,  2009, 30(16), 2785-2791.
[http://dx.doi.org/10.1002/jcc.21256] [PMID:  19399780] 
[255] 
Milani, M.; Mastrangelo, E.; Bollati, M.; Selisko, B.; Decroly, E.; Bouvet, M.; Canard, B.; Bolognesi, M. Flaviviral methyltransferase/RNA interaction: structural basis for enzyme inhibition. Antiviral Res.,  2009, 83(1), 28-34.
[http://dx.doi.org/10.1016/j.antiviral.2009.03.001] [PMID:  19501254] 
[256] 
Berendsen, H.J.C.; van der Spoel, D.; van Drunen, R. GROMACS: A message-passing parallel molecular dynamics implementation. Comput. Phys. Commun.,  1995, 91(1), 43-56.
[http://dx.doi.org/10.1016/0010-4655(95)00042-E] 
[257] 
Benmansour, F.; Trist, I.; Coutard, B.; Decroly, E.; Querat, G.; Brancale, A.; Barral, K. Discovery of novel Dengue virus NS5 methyltransferase non-nucleoside inhibitors by fragment-based drug design. Eur. J. Med. Chem.,  2017, 125, 865-880.
[http://dx.doi.org/10.1016/j.ejmech.2016.10.007] [PMID:  27750202] 
[258] 
Malet, H.; Massé, N.; Selisko, B.; Romette, J.L.; Alvarez, K.; Guillemot, J.C.; Tolou, H.; Yap, T.L.; Vasudevan, S.; Lescar, J.; Canard, B. The flavivirus polymerase as a target for drug discovery. Antiviral Res.,  2008, 80(1), 23-35.
[http://dx.doi.org/10.1016/j.antiviral.2008.06.007] [PMID:  18611413] 
[259] 
Choi, K.H. Viral polymerases. Adv. Exp. Med. Biol.,  2012, 726, 267-304.
[http://dx.doi.org/10.1007/978-1-4614-0980-9_12] [PMID:  22297518] 
[260] 
Poch, O.; Sauvaget, I.; Delarue, M.; Tordo, N. Identification of four conserved motifs among the RNA-dependent polymerase encoding elements. EMBO J.,  1989, 8(12), 3867-3874.
[http://dx.doi.org/10.1002/j.1460-2075.1989.tb08565.x] [PMID:  2555175] 
[261] 
Wu, J.; Liu, W.; Gong, P. A structural overview of RNA-dependent RNA polymerases from the Flaviviridae family. Int. J. Mol. Sci.,  2015, 16(6), 12943-12957.
[http://dx.doi.org/10.3390/ijms160612943] [PMID:  26062131] 
[262] 
De Clercq, E.; Neyts, J. Antiviral agents acting as DNA or RNA chain terminators. Handb. Exp. Pharmacol.,  2009, (189), 53-84.
[http://dx.doi.org/10.1007/978-3-540-79086-0_3] [PMID:  19048197] 
[263] 
Luo, G.; Hamatake, R.K.; Mathis, D.M.; Racela, J.; Rigat, K.L.; Lemm, J.; Colonno, R.J. De novo initiation of RNA synthesis by the RNA-dependent RNA polymerase (NS5B) of hepatitis C virus. J. Virol.,  2000, 74(2), 851-863.
[http://dx.doi.org/10.1128/JVI.74.2.851-863.2000] [PMID:  10623748] 
[264] 
Surana, P.; Satchidanandam, V.; Nair, D.T. RNA-dependent RNA polymerase of Japanese encephalitis virus binds the initiator nucleotide GTP to form a mechanistically important pre-initiation state. Nucleic Acids Res.,  2014, 42(4), 2758-2773.
[http://dx.doi.org/10.1093/nar/gkt1106] [PMID:  24293643] 
[265] 
Romette, J.; Selisko, B.; Egloff, M.; Benarroch, D.; Canard, B. Active truncated form of the RNA polymerase of flavivirus. united states patent u.s. patent 20050048472,, 2005.
[266] 
Yap, T.L.; Xu, T.; Chen, Y.L.; Malet, H.; Egloff, M.P.; Canard, B.; Vasudevan, S.G.; Lescar, J. Crystal structure of the Dengue virus RNA-dependent RNA polymerase catalytic domain at 1.85-angstrom resolution. J. Virol.,  2007, 81(9), 4753-4765.
[http://dx.doi.org/10.1128/JVI.02283-06] [PMID:  17301146] 
[267] 
Vernachio, J.H.; Bleiman, B.; Bryant, K.D.; Chamberlain, S.; Hunley, D.; Hutchins, J.; Ames, B.; Gorovits, E.; Ganguly, B.; Hall, A.; Kolykhalov, A.; Liu, Y.; Muhammad, J.; Raja, N.; Walters, C.R.; Wang, J.; Williams, K.; Patti, J.M.; Henson, G.; Madela, K.; Aljarah, M.; Gilles, A.; McGuigan, C. INX-08189, a phosphoramidate prodrug of 6-O-methyl-2′-C-methyl guanosine, is a potent inhibitor of hepatitis C virus replication with excellent pharmacokinetic and pharmacodynamic properties. Antimicrob. Agents Chemother.,  2011, 55(5), 1843-1851.
[http://dx.doi.org/10.1128/AAC.01335-10] [PMID:  21357300] 
[268] 
Migliaccio, G.; Tomassini, J.E.; Carroll, S.S.; Tomei, L.; Altamura, S.; Bhat, B.; Bartholomew, L.; Bosserman, M.R.; Ceccacci, A.; Colwell, L.F.; Cortese, R.; De Francesco, R.; Eldrup, A.B.; Getty, K.L.; Hou, X.S.; LaFemina, R.L.; Ludmerer, S.W.; MacCoss, M.; McMasters, D.R.; Stahlhut, M.W.; Olsen, D.B.; Hazuda, D.J.; Flores, O.A. Characterization of resistance to non-obligate chain-terminating ribonucleoside analogs that inhibit hepatitis C virus replication in vitro. J. Biol. Chem.,  2003, 278(49), 49164-49170.
[http://dx.doi.org/10.1074/jbc.M305041200] [PMID:  12966103] 
[269] 
Chen, Y.L.; Yokokawa, F.; Shi, P.Y. The search for nucleoside/nucleotide analog inhibitors of Dengue virus. Antiviral Res.,  2015, 122, 12-19.
[http://dx.doi.org/10.1016/j.antiviral.2015.07.010] [PMID:  26241002] 
[270] 
Yeo, K.L.; Chen, Y.L.; Xu, H.Y.; Dong, H.; Wang, Q.Y.; Yokokawa, F.; Shi, P.Y. Synergistic suppression of Dengue virus replication using a combination of nucleoside analogs and nucleoside synthesis inhibitors. Antimicrob. Agents Chemother.,  2015, 59(4), 2086-2093.
[http://dx.doi.org/10.1128/AAC.04779-14] [PMID:  25624323] 
[271] 
Lee, J.C.; Tseng, C.K.; Wu, Y.H.; Kaushik-Basu, N.; Lin, C.K.; Chen, W.C.; Wu, H.N. Characterization of the activity of 2′-C-methylcytidine against dengue virus replication. Antiviral Res.,  2015, 116, 1-9.
[http://dx.doi.org/10.1016/j.antiviral.2015.01.002] [PMID:  25614455] 
[272] 
Eyer, L.; Nencka, R.; Huvarová, I.; Palus, M.; Joao Alves, M.; Gould, E.A.; De Clercq, E.; Růžek, D. Nucleoside Inhibitors of Zika Virus. J. Infect. Dis.,  2016, 214(5), 707-711.
[http://dx.doi.org/10.1093/infdis/jiw226] [PMID:  27234417] 
[273] 
Potisopon, S.; Ferron, F.; Fattorini, V.; Selisko, B.; Canard, B. Substrate selectivity of Dengue and Zika virus NS5 polymerase towards 2′-modified nucleotide analogues. Antiviral Res.,  2017, 140, 25-36.
[http://dx.doi.org/10.1016/j.antiviral.2016.12.021] [PMID:  28041959] 
[274] 
Denning, J.; Cornpropst, M.; Flach, S.D.; Berrey, M.M.; Symonds, W.T. Pharmacokinetics, safety, and tolerability of GS-9851, a nucleotide analog polymerase inhibitor for hepatitis C virus, following single ascending doses in healthy subjects. Antimicrob. Agents Chemother.,  2013, 57(3), 1201-1208.
[http://dx.doi.org/10.1128/AAC.01262-12] [PMID:  23262999] 
[275] 
Murakami, E.; Tolstykh, T.; Bao, H.; Niu, C.; Steuer, H.M.; Bao, D.; Chang, W.; Espiritu, C.; Bansal, S.; Lam, A.M.; Otto, M.J.; Sofia, M.J.; Furman, P.A. Mechanism of activation of PSI-7851 and its diastereoisomer PSI-7977. J. Biol. Chem.,  2010, 285(45), 34337-34347.
[http://dx.doi.org/10.1074/jbc.M110.161802] [PMID:  20801890] 
[276] 
Gan, C.S.; Lim, S.K.; Chee, C.F.; Yusof, R.; Heh, C.H. Sofosbuvir as treatment against dengue? Chem. Biol. Drug Des., 2017.
[http://dx.doi.org/10.1111/cbdd.13091]] [PMID:  28834304] 
[277] 
Xu, H.T.; Colby-Germinario, S.P.; Hassounah, S.A.; Fogarty, C.; Osman, N.; Palanisamy, N.; Han, Y.; Oliveira, M.; Quan, Y.; Wainberg, M.A. Evaluation of Sofosbuvir (β-D-2′-deoxy-2′-α-fluoro-2′-β-C-methyluridine) as an inhibitor of Dengue virus replication<sup/>. Sci. Rep.,  2017, 7(1), 6345.
[http://dx.doi.org/10.1038/s41598-017-06612-2] [PMID:  28740124] 
[278] 
Nguyen, N.M.; Tran, C.N.; Phung, L.K.; Duong, K.T. Huynh, Hle.A.; Farrar, J.; Nguyen, Q.T.; Tran, H.T.; Nguyen, C.V.; Merson, L.; Hoang, L.T.; Hibberd, M.L.; Aw, P.P.; Wilm, A.; Nagarajan, N.; Nguyen, D.T.; Pham, M.P.; Nguyen, T.T.; Javanbakht, H.; Klumpp, K.; Hammond, J.; Petric, R.; Wolbers, M.; Nguyen, C.T.; Simmons, C.P. A randomized, double-blind placebo controlled trial of balapiravir, a polymerase inhibitor, in adult dengue patients. J. Infect. Dis.,  2013, 207(9), 1442-1450.
[http://dx.doi.org/10.1093/infdis/jis470] [PMID:  22807519] 
[279] 
Yin, Z.; Chen, Y.L.; Schul, W.; Wang, Q.Y.; Gu, F.; Duraiswamy, J.; Kondreddi, R.R.; Niyomrattanakit, P.; Lakshminarayana, S.B.; Goh, A.; Xu, H.Y.; Liu, W.; Liu, B.; Lim, J.Y.; Ng, C.Y.; Qing, M.; Lim, C.C.; Yip, A.; Wang, G.; Chan, W.L.; Tan, H.P.; Lin, K.; Zhang, B.; Zou, G.; Bernard, K.A.; Garrett, C.; Beltz, K.; Dong, M.; Weaver, M.; He, H.; Pichota, A.; Dartois, V.; Keller, T.H.; Shi, P.Y. An adenosine nucleoside inhibitor of Dengue virus. Proc. Natl. Acad. Sci. USA,  2009, 106(48), 20435-20439.
[http://dx.doi.org/10.1073/pnas.0907010106] [PMID:  19918064] 
[280] 
Chen, Y.L.; Yin, Z.; Lakshminarayana, S.B.; Qing, M.; Schul, W.; Duraiswamy, J.; Kondreddi, R.R.; Goh, A.; Xu, H.Y.; Yip, A.; Liu, B.; Weaver, M.; Dartois, V.; Keller, T.H.; Shi, P.Y. Inhibition of dengue virus by an ester prodrug of an adenosine analog. Antimicrob. Agents Chemother.,  2010, 54(8), 3255-3261.
[http://dx.doi.org/10.1128/AAC.00397-10] [PMID:  20516277] 
[281] 
Wu, R.; Smidansky, E.D.; Oh, H.S.; Takhampunya, R.; Padmanabhan, R.; Cameron, C.E.; Peterson, B.R. Synthesis of a 6-methyl-7-deaza analogue of adenosine that potently inhibits replication of polio and dengue viruses. J. Med. Chem.,  2010, 53(22), 7958-7966.
[http://dx.doi.org/10.1021/jm100593s] [PMID:  20964406] 
[282] 
Eyer, L.; Zouharová, D.; Širmarová, J.; Fojtíková, M.; Štefánik, M.; Haviernik, J.; Nencka, R.; de Clercq, E.; Růžek, D. Antiviral activity of the adenosine analogue BCX4430 against West Nile virus and tick-borne flaviviruses. Antiviral Res.,  2017, 142, 63-67.
[http://dx.doi.org/10.1016/j.antiviral.2017.03.012] [PMID:  28336346] 
[283] 
Julander, J.G.; Bantia, S.; Taubenheim, B.R.; Minning, D.M.; Kotian, P.; Morrey, J.D.; Smee, D.F.; Sheridan, W.P.; Babu, Y.S. BCX4430, a novel nucleoside analog, effectively treats yellow fever in a Hamster model. Antimicrob. Agents Chemother.,  2014, 58(11), 6607-6614.
[http://dx.doi.org/10.1128/AAC.03368-14] [PMID:  25155605] 
[284] 
Julander, J.G.; Siddharthan, V.; Evans, J.; Taylor, R.; Tolbert, K.; Apuli, C.; Stewart, J.; Collins, P.; Gebre, M.; Neilson, S.; Van Wettere, A.; Lee, Y.M.; Sheridan, W.P.; Morrey, J.D.; Babu, Y.S. Efficacy of the broad-spectrum antiviral compound BCX4430 against Zika virus in cell culture and in a mouse model. Antiviral Res.,  2017, 137, 14-22.
[http://dx.doi.org/10.1016/j.antiviral.2016.11.003] [PMID:  27838352] 
[285] 
Taylor, R.; Kotian, P.; Warren, T.; Panchal, R.; Bavari, S.; Julander, J.; Dobo, S.; Rose, A.; El-Kattan, Y.; Taubenheim, B.; Babu, Y.; Sheridan, W.P. BCX4430 - A broad-spectrum antiviral adenosine nucleoside analog under development for the treatment of Ebola virus disease. J. Infect. Public Health,  2016, 9(3), 220-226.
[http://dx.doi.org/10.1016/j.jiph.2016.04.002] [PMID:  27095300] 
[286] 
Warren, T.K.; Wells, J.; Panchal, R.G.; Stuthman, K.S.; Garza, N.L.; Van Tongeren, S.A.; Dong, L.; Retterer, C.J.; Eaton, B.P.; Pegoraro, G.; Honnold, S.; Bantia, S.; Kotian, P.; Chen, X.; Taubenheim, B.R.; Welch, L.S.; Minning, D.M.; Babu, Y.S.; Sheridan, W.P.; Bavari, S. Protection against filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430. Nature,  2014, 508(7496), 402-405.
[http://dx.doi.org/10.1038/nature13027] [PMID:  24590073] 
[287] 
Tichý, M.; Pohl, R.; Xu, H.Y.; Chen, Y.L.; Yokokawa, F.; Shi, P.Y.; Hocek, M. Synthesis and antiviral activity of 4,6-disubstituted pyrimido[4,5-b]indole ribonucleosides. Bioorg. Med. Chem.,  2012, 20(20), 6123-6133.
[http://dx.doi.org/10.1016/j.bmc.2012.08.021] [PMID:  22985963] 
[288] 
Tichý, M.; Pohl, R.; Tloušt’ová, E.; Weber, J.; Bahador, G.; Lee, Y.J.; Hocek, M. Synthesis and biological activity of benzo-fused 7-deazaadenosine analogues. 5- and 6-substituted 4-amino- or 4-alkylpyrimido[4,5-b]indole ribonucleosides. Bioorg. Med. Chem.,  2013, 21(17), 5362-5372.
[http://dx.doi.org/10.1016/j.bmc.2013.06.011] [PMID:  23827234] 
[289] 
Chatelain, G.; Debing, Y.; De Burghgraeve, T.; Zmurko, J.; Saudi, M.; Rozenski, J.; Neyts, J.; Van Aerschot, A. In search of flavivirus inhibitors: evaluation of different tritylated nucleoside analogues. Eur. J. Med. Chem.,  2013, 65, 249-255.
[http://dx.doi.org/10.1016/j.ejmech.2013.04.034] [PMID:  23721953] 
[290] 
De Burghgraeve, T.; Selisko, B.; Kaptein, S.; Chatelain, G.; Leyssen, P.; Debing, Y.; Jacobs, M.; Van Aerschot, A.; Canard, B.; Neyts, J. 3′,5'Di-O-trityluridine inhibits in vitro flavivirus replication. Antiviral Res.,  2013, 98(2), 242-247.
[http://dx.doi.org/10.1016/j.antiviral.2013.01.011] [PMID:  23470860] 
[291] 
McGuigan, C.; Serpi, M.; Slusarczyk, M.; Ferrari, V.; Pertusati, F.; Meneghesso, S.; Derudas, M.; Farleigh, L.; Zanetta, P.; Bugert, J. Anti-flavivirus activity of different tritylated pyrimidine and purine nucleoside analogues. Chem. Open,  2016, 5(3), 227-235.
[http://dx.doi.org/10.1002/open.201500216] [PMID:  27551659] 
[292] 
Saudi, M.; Zmurko, J.; Kaptein, S.; Rozenski, J.; Neyts, J.; Van Aerschot, A. In search of Flavivirus inhibitors part 2: tritylated, diphenylmethylated and other alkylated nucleoside analogues. Eur. J. Med. Chem.,  2014, 76, 98-109.
[http://dx.doi.org/10.1016/j.ejmech.2014.02.011] [PMID:  24583349] 
[293] 
Yin, Z.; Chen, Y.L.; Kondreddi, R.R.; Chan, W.L.; Wang, G.; Ng, R.H.; Lim, J.Y.; Lee, W.Y.; Jeyaraj, D.A.; Niyomrattanakit, P.; Wen, D.; Chao, A.; Glickman, J.F.; Voshol, H.; Mueller, D.; Spanka, C.; Dressler, S.; Nilar, S.; Vasudevan, S.G.; Shi, P.Y.; Keller, T.H. N-sulfonylanthranilic acid derivatives as allosteric inhibitors of dengue viral RNA-dependent RNA polymerase. J. Med. Chem.,  2009, 52(24), 7934-7937.
[http://dx.doi.org/10.1021/jm901044z] [PMID:  20014868] 
[294] 
Niyomrattanakit, P.; Chen, Y.L.; Dong, H.; Yin, Z.; Qing, M.; Glickman, J.F.; Lin, K.; Mueller, D.; Voshol, H.; Lim, J.Y.; Nilar, S.; Keller, T.H.; Shi, P.Y. Inhibition of dengue virus polymerase by blocking of the RNA tunnel. J. Virol.,  2010, 84(11), 5678-5686.
[http://dx.doi.org/10.1128/JVI.02451-09] [PMID:  20237086] 
[295] 
Noble, C.G.; Lim, S.P.; Chen, Y.L.; Liew, C.W.; Yap, L.; Lescar, J.; Shi, P.Y. Conformational flexibility of the Dengue virus RNA-dependent RNA polymerase revealed by a complex with an inhibitor. J. Virol.,  2013, 87(9), 5291-5295.
[http://dx.doi.org/10.1128/JVI.00045-13] [PMID:  23408636] 
[296] 
Noble, C.G.; Lim, S.P.; Arora, R.; Yokokawa, F.; Nilar, S.; Seh, C.C.; Wright, S.K.; Benson, T.E.; Smith, P.W.; Shi, P.Y. A conserved pocket in the Dengue virus polymerase identified through fragment-based screening. J. Biol. Chem.,  2016, 291(16), 8541-8548.
[http://dx.doi.org/10.1074/jbc.M115.710731] [PMID:  26872970] 
[297] 
Yokokawa, F.; Nilar, S.; Noble, C.G.; Lim, S.P.; Rao, R.; Tania, S.; Wang, G.; Lee, G.; Hunziker, J.; Karuna, R.; Manjunatha, U.; Shi, P.Y.; Smith, P.W. Discovery of potent non-nucleoside inhibitors of Dengue viral RNA-dependent RNA polymerase from a fragment hit using structure-based drug design. J. Med. Chem.,  2016, 59(8), 3935-3952.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00143] [PMID:  26984786] 
[298] 
Lim, S.P.; Noble, C.G.; Seh, C.C.; Soh, T.S.; El Sahili, A.; Chan, G.K.; Lescar, J.; Arora, R.; Benson, T.; Nilar, S.; Manjunatha, U.; Wan, K.F.; Dong, H.; Xie, X.; Shi, P.Y.; Yokokawa, F. Potent allosteric Dengue virus NS5 polymerase inhibitors: mechanism of action and resistance profiling. PLoS Pathog.,  2016, 12(8), e1005737.
[http://dx.doi.org/10.1371/journal.ppat.1005737] [PMID:  27500641] 
[299] 
Tarantino, D.; Cannalire, R.; Mastrangelo, E.; Croci, R.; Querat, G.; Barreca, M.L.; Bolognesi, M.; Manfroni, G.; Cecchetti, V.; Milani, M. Targeting flavivirus RNA dependent RNA polymerase through a pyridobenzothiazole inhibitor. Antiviral Res.,  2016, 134, 226-235.
[http://dx.doi.org/10.1016/j.antiviral.2016.09.007] [PMID:  27649989] 
[300] 
Wagstaff, K.M.; Sivakumaran, H.; Heaton, S.M.; Harrich, D.; Jans, D.A. Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and Dengue virus. Biochem. J.,  2012, 443(3), 851-856.
[http://dx.doi.org/10.1042/BJ20120150] [PMID:  22417684] 
[301] 
Tay, M.Y.; Fraser, J.E.; Chan, W.K.; Moreland, N.J.; Rathore, A.P.; Wang, C.; Vasudevan, S.G.; Jans, D.A. Nuclear localization of Dengue virus (DENV) 1-4 non-structural protein 5; protection against all 4 DENV serotypes by the inhibitor Ivermectin. Antiviral Res.,  2013, 99(3), 301-306.
[http://dx.doi.org/10.1016/j.antiviral.2013.06.002] [PMID:  23769930] 
[302] 
Fraser, J.E.; Watanabe, S.; Wang, C.; Chan, W.K.; Maher, B.; Lopez-Denman, A.; Hick, C.; Wagstaff, K.M.; Mackenzie, J.M.; Sexton, P.M.; Vasudevan, S.G.; Jans, D.A. A nuclear transport inhibitor that modulates the unfolded protein response and provides in vivo protection against lethal dengue virus infection. J. Infect. Dis.,  2014, 210(11), 1780-1791.
[http://dx.doi.org/10.1093/infdis/jiu319] [PMID:  24903662] 
[303] 
Vincetti, P.; Caporuscio, F.; Kaptein, S.; Gioiello, A.; Mancino, V.; Suzuki, Y.; Yamamoto, N.; Crespan, E.; Lossani, A.; Maga, G.; Rastelli, G.; Castagnolo, D.; Neyts, J.; Leyssen, P.; Costantino, G.; Radi, M. Discovery of multitarget antivirals acting on both the Dengue virus NS5-NS3 interaction and the host Src/Fyn kinases. J. Med. Chem.,  2015, 58(12), 4964-4975.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00108] [PMID:  26039671] 
[304] 
Carocci, M.; Hinshaw, S.M.; Rodgers, M.A.; Villareal, V.A.; Burri, D.J.; Pilankatta, R.; Maharaj, N.P.; Gack, M.U.; Stavale, E.J.; Warfield, K.L.; Yang, P.L. The bioactive lipid 4-hydroxyphenyl retinamide inhibits flavivirus replication. Antimicrob. Agents Chemother.,  2015, 59(1), 85-95.
[http://dx.doi.org/10.1128/AAC.04177-14] [PMID:  25313218] 
[305] 
Thenin-Houssier, S.; Valente, S.T.S. HIV-1 capsid inhibitors as antiretroviral agents. Curr. HIV Res.,  2016, 14(3), 270-282.
[http://dx.doi.org/10.2174/1570162X14999160224103555] [PMID:  26957201] 
[306] 
w.h.o.neglected tropical diseases − summary, http://www.who.int/neglected_diseases/diseases/summary/en/
Rights & Permissions Print Cite
Article Metrics
98
Journal Information
For Authors
For Editors
For Reviewers
Explore Articles
Open Access
Open Access Articles
For Visitors
DOI https://dx.doi.org/10.2174/0929867326666181204155336	Print ISSN 0929-8673
Publisher Name Bentham Science Publisher	Online ISSN 1875-533X
Current Medicinal Chemistry

Discovery of Dengue Virus Inhibitors

Abstract

Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.

Approaches to the Treatment of Chronic Inflammation

Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications

Chalcogen-modified nucleic acid analogues

Current Medicinal Chemistry

Discovery of Dengue Virus Inhibitors

Abstract

Call for Papers in Thematic Issues

Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.

Approaches to the Treatment of Chronic Inflammation

Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications

Chalcogen-modified nucleic acid analogues

Related Journals

Related Books

Related Articles
