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Current Molecular Pharmacology

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ISSN (Print): 1874-4672
ISSN (Online): 1874-4702

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Research Article

Grp94 Inhibitor HCP1 Suppressed the Replication of SVA in BHK-21 Cells and PK-15 Cells

Author(s): Shuo Wang, XiaoLing Cui, Ren Hui, Wen Yao, BaoXiang Zhao, Jun Li* and JunYing Miao*

Volume 17, 2024

Published on: 23 August, 2023

Article ID: e050723218413 Pages: 9

DOI: 10.2174/1874467217666230705120856

open_access

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Abstract

Background: Glucoregulatory protein 94 (Grp94) is necessary for the post-viral life cycle and plays a quality control role in viral proteins, but the role of Grp94 in regulating viral replication in host cells is not well known. Therefore, finding a compound that can regulate Grp94 will help us to study the mechanism of viral replication. Previously, we synthesized a coumarin pyrazoline derivative HCP1 that is an effective inhibitor of Grp94. We suppose that HCP1 may inhibit viral replication.

Objective: This study aimed to investigate the effect of HCP1 on the replication ability of Senecavirus A (SVA), so as to provide a target and a leading compound for revealing the pathogenic mechanism of the virus and developing antiviral drugs.

Methods: Rat cell lines BHK-21 and porcine cell lines PK-15 were infected with SVA, and the infected cells were treated with different concentrations of HCP1. The cell viability (CCK-8), virus titer (TCID50), autophagy level, and Grp94 expression were measured.

Results: The results showed that a low concentration of HCP1 decreased viral titer and viral load in BHK-21 and PK-15 cells, and 5μM HCP1 significantly decreased the expression of SVA VP2 protein. In addition, SVA infection can lead to an increased level of autophagy, and HCP1 can inhibit host cell autophagy caused by SVA infection, thereby inhibiting viral replication and infection.

Conclusion: These findings reveal that Grp94 is a key factor in controlling SVA replication, and its inhibitor HCP1 suppresses SVA replication by inhibiting the increase of Grp94 protein level and autophagy induced by SVA. This study will contribute to the development of a new class of small-molecule antiviral drugs.

Keywords: Senecavirus A, Grp94, HCP1, Virus replication, Autophagy, Infection, Endoplasmic Reticulum (ER).

[1]
Gewirth, D.T. Paralog Specific Hsp90 Inhibitors - A Brief History and a Bright Future. Curr. Top. Med. Chem., 2016, 16(25), 2779-2791.
[http://dx.doi.org/10.2174/1568026616666160413141154] [PMID: 27072700]
[2]
Hoter, A.; El-Sabban, M.; Naim, H. The HSP90 Family: Structure, Regulation, Function, and Implications in Health and Disease. Int. J. Mol. Sci., 2018, 19(9), 2560.
[http://dx.doi.org/10.3390/ijms19092560] [PMID: 30158430]
[3]
Ansa-Addo, E.A.; Thaxton, J.; Hong, F.; Wu, B.X.; Zhang, Y.; Fugle, C.W.; Metelli, A.; Riesenberg, B.; Williams, K.; Gewirth, D.T.; Chiosis, G.; Liu, B.; Li, Z. Clients and Oncogenic Roles of Molecular Chaperone gp96/grp94. Curr. Top. Med. Chem., 2016, 16(25), 2765-2778.
[http://dx.doi.org/10.2174/1568026616666160413141613] [PMID: 27072698]
[4]
Kim, D.S.; Li, B.; Rhew, K.Y.; Oh, H.W.; Lim, H.D.; Lee, W.; Chae, H.J.; Kim, H.R. The regulatory mechanism of 4-phenylbutyric acid against ER stress-induced autophagy in human gingival fibroblasts. Arch. Pharm. Res., 2012, 35(7), 1269-1278.
[http://dx.doi.org/10.1007/s12272-012-0718-2] [PMID: 22864750]
[5]
Rothan, H.A.H.A. Small molecule grp94 inhibitors with antiviral activity against Dengue and Zika virus. Antiviral Res., 2019, 171, 104590-104590.
[http://dx.doi.org/10.1016/j.antiviral.2019.104590] [PMID: 31421166]
[6]
Hales, LM Complete genome sequence analysis of Seneca Valley virus-001, a novel oncolytic picornavirus. J Gen Virol.,, 2008, 89, 1265-1275.
[7]
Venkataraman, S.; Reddy, S.P.; Loo, J.; Idamakanti, N.; Hallenbeck, P.L.; Reddy, V.S. Crystallization and preliminary X-ray diffraction studies of Seneca Valley Virus-001, a new member of the Picornaviridae family. Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun., 2008, 64(4), 293-296.
[http://dx.doi.org/10.1107/S1744309108006921] [PMID: 18391430]
[8]
Arzt, J.; Bertram, M.R.; Vu, L.T.; Pauszek, S.J.; Hartwig, E.J.; Smoliga, G.R.; Palinski, R.; Stenfeldt, C.; Fish, I.H.; Hoang, B.H.; Phuong, N.T.; Hung, V.V.; Vu, P.P.; Dung, N.K.; Dong, P.V.; Tien, N.N.; Dung, D.H. First Detection and Genome Sequence of Senecavirus A in Vietnam. Microbiol. Resour. Announc., 2019, 8(3), e01247-18.
[http://dx.doi.org/10.1128/MRA.01247-18] [PMID: 30687818]
[9]
Canning, P.; Canon, A.; Bates, J.L.; Gerardy, K.; Linhares, D.C.L.; Piñeyro, P.E.; Schwartz, K.J.; Yoon, K.J.; Rademacher, C.J.; Holtkamp, D.; Karriker, L. Neonatal Mortality, Vesicular Lesions and Lameness Associated with Senecavirus A in a U.S. Sow Farm. Transbound. Emerg. Dis., 2016, 63(4), 373-378.
[http://dx.doi.org/10.1111/tbed.12516] [PMID: 27213868]
[10]
Saeng-chuto, K.; Rodtian, P.; Temeeyasen, G.; Wegner, M.; Nilubol, D. The first detection of Senecavirus A in pigs in Thailand, 2016. Transbound. Emerg. Dis., 2018, 65(1), 285-288.
[http://dx.doi.org/10.1111/tbed.12654] [PMID: 28474854]
[11]
Poirier, J.T.; Dobromilskaya, I.; Moriarty, W.F.; Peacock, C.D.; Hann, C.L.; Rudin, C.M. Selective tropism of Seneca Valley virus for variant subtype small cell lung cancer. J. Natl. Cancer Inst., 2013, 105(14), 1059-1065.
[http://dx.doi.org/10.1093/jnci/djt130] [PMID: 23739064]
[12]
Burke, M. Oncolytic Seneca Valley Virus: past perspectives and future directions. Oncolytic Virother., 2016, 5, 81-89.
[http://dx.doi.org/10.2147/OV.S96915] [PMID: 27660749]
[13]
Hou, L.; Dong, J.; Zhu, S.; Yuan, F.; Wei, L.; Wang, J.; Quan, R.; Chu, J.; Wang, D.; Jiang, H.; Xi, Y.; Li, Z.; Song, H.; Guo, Y.; Lv, M.; Liu, J. Seneca valley virus activates autophagy through the PERK and ATF6 UPR pathways. Virology, 2019, 537, 254-263.
[http://dx.doi.org/10.1016/j.virol.2019.08.029] [PMID: 31539773]
[14]
Houston, E.; Temeeyasen, G.; Piñeyro, P.E. Comprehensive review on immunopathogenesis, diagnostic and epidemiology of Senecavirus A. Virus Res., 2020, 286, 198038-198038.
[http://dx.doi.org/10.1016/j.virusres.2020.198038] [PMID: 32479975]
[15]
Qian, S.; Fan, W.; Liu, T.; Wu, M.; Zhang, H.; Cui, X.; Zhou, Y.; Hu, J.; Wei, S.; Chen, H.; Li, X.; Qian, P. Seneca Valley Virus Suppresses Host Type I Interferon Production by Targeting Adaptor Proteins MAVS, TRIF, and TANK for Cleavage. J. Virol., 2017, 91(16), e00823-17.
[http://dx.doi.org/10.1128/JVI.00823-17] [PMID: 28566380]
[16]
Ren, H.; Yao, W.; Wei, Q.; Zhang, J.; Zhao, B.; Miao, J. Identification of a new autophagy inhibitor targeting lipid droplets in vascular endothelial cells. Biochem. Biophys. Res. Commun., 2021, 571, 195-200.
[http://dx.doi.org/10.1016/j.bbrc.2021.07.078] [PMID: 34330064]
[17]
Wei, Q.; Ning, J.Y.; Dai, X.; Gao, Y.D.; Su, L.; Zhao, B.X.; Miao, J.Y. Discovery of novel HSP90 inhibitors that induced apoptosis and impaired autophagic flux in A549 lung cancer cells. Eur. J. Med. Chem., 2018, 145, 551-558.
[http://dx.doi.org/10.1016/j.ejmech.2018.01.024] [PMID: 29339250]
[18]
Wu, X. W.S.L.C., CRISPR/Cas9-Mediated Knockout of the Dicer and Ago2 Genes in BHK-21 Cell Promoted Seneca Virus A Replication and Enhanced Autophagy. Front. Cell. Infect. Microbiol., 2022.
[19]
Wen, W.; Li, X.; Yin, M.; Wang, H.; Qin, L.; Li, H.; Liu, W.; Zhao, Z.; Zhao, Q.; Chen, H.; Hu, J.; Qian, P. Selective autophagy receptor SQSTM1/ p62 inhibits Seneca Valley virus replication by targeting viral VP1 and VP3. Autophagy, 2021, 17(11), 3763-3775.
[http://dx.doi.org/10.1080/15548627.2021.1897223] [PMID: 33719859]
[20]
Gottlieb, R.A.; Andres, A.M.; Sin, J.; Taylor, D.P.J. Untangling autophagy measurements: all fluxed up. Circ. Res., 2015, 116(3), 504-514.
[http://dx.doi.org/10.1161/CIRCRESAHA.116.303787] [PMID: 25634973]
[21]
De Palma, A.M.; Vliegen, I.; De Clercq, E.; Neyts, J. Selective inhibitors of picornavirus replication. Med. Res. Rev., 2008, 28(6), 823-884.
[http://dx.doi.org/10.1002/med.20125] [PMID: 18381747]
[22]
Boyle, K.B.; Randow, F. The role of ‘eat-me’ signals and autophagy cargo receptors in innate immunity. Curr. Opin. Microbiol., 2013, 16(3), 339-348.
[http://dx.doi.org/10.1016/j.mib.2013.03.010] [PMID: 23623150]
[23]
Valk, P.J.M.; Vankan, Y.; Joosten, M.; Jenkins, N.A.; Copeland, N.G.; Löwenberg, B.; Delwel, R. Retroviral insertions in Evi12, a novel common virus integration site upstream of Tra1/Grp94, frequently coincide with insertions in the gene encoding the peripheral cannabinoid receptor Cnr2. J. Virol., 1999, 73(5), 3595-3602.
[http://dx.doi.org/10.1128/JVI.73.5.3595-3602.1999] [PMID: 10196250]
[24]
Lee, S.H.; Song, R.; Lee, M.N.; Kim, C.S.; Lee, H.; Kong, Y.Y.; Kim, H.; Jang, S.K. A molecular chaperone glucose-regulated protein 94 blocks apoptosis induced by virus infection. Hepatology, 2008, 47(3), 854-866.
[http://dx.doi.org/10.1002/hep.22107] [PMID: 18273841]
[25]
Mayer, M.P. Recruitment of Hsp70 chaperones: a crucial part of viral survival strategies. Rev. Physiol. Biochem. Pharmacol., 2005, 153, 1-46.
[http://dx.doi.org/10.1007/s10254-004-0025-5] [PMID: 15243813]
[26]
Kaur, M.; Kohli, S.; Sandhu, S.; Bansal, Y.; Bansal, G. Coumarin: a promising scaffold for anticancer agents. Anticancer. Agents Med. Chem., 2015, 15(8), 1032-1048.
[http://dx.doi.org/10.2174/1871520615666150101125503] [PMID: 25553437]
[27]
Sashidhara, K.V.; Kumar, A.; Kumar, M.; Sonkar, R.; Bhatia, G.; Khanna, A.K. Novel coumarin derivatives as potential antidyslipidemic agents. Bioorg. Med. Chem. Lett., 2010, 20(14), 4248-4251.
[http://dx.doi.org/10.1016/j.bmcl.2010.05.023] [PMID: 20542691]
[28]
Bhattarai, N.; Kumbhar, A.A.; Pokharel, Y.R.; Yadav, P.N. Anticancer potential of coumarin and its derivatives. Mini Rev. Med. Chem., 2021, 21(19), 2996-3029.
[http://dx.doi.org/10.2174/18755607MTE1uMjAm4] [PMID: 33820507]

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