Book Volume 6
Page: vii-viii (2)
Author: Allen B. Reitz, Atta-ur-Rahman and M. Iqbal Choudhary
Page: ix-xiii (5)
Author: Allen B. Reitz, Atta-ur-Rahman and M. Iqbal Choudhary
AntiViral-HyperActivation Limiting Therapeutics (AV-HALTs): A New Class of Antiviral Drugs
Page: 3-21 (19)
Author: Franco Lori, Julianna Lisziewicz, Davide De Forni and Mike Stevens
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This paper will review recent discoveries in the field of viral pathogenesis and the development of a new antiretroviral class known as AntiViral-HyperActivation Limiting Therapeutics (AV-HALTs) that has been specifically designed in response to these findings. AV-HALTs are characterized by the combination of two distinct activities – the direct inhibition of viral replication (antiviral activity) and the reduction of excessive chronic immune system hyperactivation (hyperactivation limiting effect). These two effects can be achieved by combining two drugs (a first-generation AV-HALT) or by a single molecule (second-generation AV-HALTs).
The medical need for AV-HALTs is best illustrated in the treatment of the Human ImmunoDeficiency Virus Type 1 (HIV-1). Paradoxically, it is the chronic, excessive hyperactivation of the immune system, resulting in cellular hyperproliferation and systemic inflammation – throughout the course of HIV disease – that is now recognized as the major driver of not only the continual loss of CD4+ T cells and progression to the Acquired Immunodeficiency Syndrome (AIDS), but also of the emergence of both AIDS-defining and non-AIDS-defining events that negatively impact upon both morbidity and mortality despite otherwise successful (ie, fully virus suppressive) HIV therapy. This review will focus upon the establishment of the human proof of concept for AV-HALTs using a two-drug, first-generation AV-HALT (VS411) and the development of single-molecule, second-generation AV-HALTs for the treatment of HIV-1 disease and other chronic viral infections.
The Efficacy of Viral Capsid Inhibitors in Human Enterovirus Infection and Associated Diseases
Page: 22-40 (19)
Author: Shin-Ru Shih, Gary Brewer, Peng-Nien Huang, Kuo-Feng Weng, Chin Li, Hongtao Wang, Tzu-Chun Chen and Mei-Ling Li
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Enteroviruses are members of picornavirus family which causes diverse and severe diseases in humans and animals. Clinical manifestations of enterovirus infections include fever, hand, foot, and mouth disease, and herpangina. Enteroviruses also cause potentially severe and life-threatening infections such as meningitis, encephalitis, myocarditis, polio-like syndrome, and neonatal sepsis. With the emergence of enterovirus all over the world as the major causative agent of HFMD fatalities in recent years and in the absence of any effective anti-enteroviral therapy, there is clearly a need to find a specific antiviral therapy. Steps such as viral attachment, uncoating, viral RNA replication, and protein synthesis in the replication cycle can serve as potential targets for antiviral agents. Agents targeted at viral protein 1 (VP1), a relatively conserved capsid structure mediating viral adsorption and uncoating process, is of great potential to be anti-enterovirus drugs.
Recently, considerable efforts have been made in the development of antiviral compounds targeting the capsid protein of enterovirus. This review summarizes the development of small molecules targeting enteroviral capsid protein as effective antiviral therapy.
Antibiotic Properties and Applications of Lactoferrin
Page: 41-61 (21)
Author: Eugene D. Weinberg
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Lactoferrin (Lf), a mammalian iron scavenging defense protein, constitutively is present in exocrine secretions that consistently are exposed to microbial flora: milk, tears, tubotympanum and nasal exudate, saliva, bronchial mucus, gastrointestinal fluids, cervicovaginal mucus, and seminal fluid. Additionally, Lf is promptly delivered by circulating neutrophils to sites of microbial invasion. At these sites, the protein effectively scavenges iron at pH values as low as 3.5.
Recombinant bovine and human lactoferrin is now available for development into nutraceutical/preservative/pharmaceutical products. Among conditions for which the products are being investigated are: angiogenesis; bone remodeling; food preservation; infection in animals, humans, plants; neoplasia in animals, humans; inflammation in intestine, joints; wound healing; as well as enhancement of antimicrobial and antineoplastic drugs, and prevention of iron induced oxidation of milk formula.
The Targets of Currently Used Antibacterial Agents: Lessons for Drug Discovery
Page: 62-96 (35)
Author: Roland P. Lange, Hans H. Locher, Pierre C. Wyss and Rudolf L. Then
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Based on the mode of action of antibacterial drugs currently used, targets can be defined as distinct cellular constituents such as enzymes, enzyme substrates, RNA, DNA, and membranes which exhibit very specific binding sites at the surface of these components or at the interface of macromolecular complexes assembled in the cell. Intriguingly, growth inhibition or even complete loss of bacterial viability is often the result of a cascade of events elicited upon treatment with an antibacterial agent. In addition, their mode of action frequently involves more than one single target.
A comprehensive description of the targets exploited so far by commercialized antibacterial agents, including anti-mycobacterial agents, is given. The number of targets exploited so far by commercial antibacterial agents is estimated to be about 40. The most important biosynthetic pathways and cellular structures affected by antibacterial drugs are the cell wall biosynthesis, protein biosynthesis, DNA per se, replication, RNA per se, transcription and the folate biosynthetic pathway.
The disillusionment with the genomics driven antibacterial drug discovery is a result of the restrictive definition of targets as products of essential and conserved genes. Emphasis is made to not only focus on proteins as potential drug targets, but increase efforts and devise screening technologies to discover new agents interacting with different RNA species, DNA, new protein families or macromolecular complexes of these constituents.
Chemotherapy of Leishmaniasis: Past, Present and Future
Page: 97-130 (34)
Author: Jyotsna Mishra, Anubha Saxena and Sarman Singh
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Leishmaniasis is a parasitic disease caused by hemoflagellate, Leishmania spp. The parasite is transmitted through the bites of an infected female phlebotomine sandfly. Leishmaniasis is prevalent throughout the world and in at least 88 countries. For its treatment, nearly 25 compounds are reported to have anti-leishmanial effects but not all are in use. Pentavalent antimony compounds had remained mainstay for nearly 75 years. However, emergence of resistance to this drug, led to the use of other compounds such as -Amphotericin B, Pentamidine, Paromomycin, Allopurinol etc. Amphotericin B, an antifungal macrolide polyene is characterized by the hydrophilic polyhydroxyl and hydrophobic polyene faces on it long axis which acts on membrane sterols resulting in parasite cell lysis. Presently, it is the only drug with highest cure rate. Other anti-fungals like ketoconazole, fluconazole and terbinafine are found less effective. Recently, anticancer alkylphosphocholines have been found to be the most effective oral compounds. These act as membrane synthetic ether-lipid analogues, and consist of alkyl chains in the lipid portions. Most promising of these are miltefosine (hexadecylphosphocholine), Edelfosine (ET-18-OCH3) and Ilmofosine (BM 41.440). However, the recent focus has been on identifying newer therapeutic targets in the parasite such as DNA topoisomerases. The present review describes the current understanding of different drugs against leishmaniasis, their chemistry, mode of action and the mechanism of resistance in the parasite. Future perspectives in the area of new anti-leishmanial drug targets are also enumerated. However, due to the vastness of the topic main emphasis is given on visceral leishmaniasis.
Antimicrobial Peptides in Oral Cancer: Review Article
Page: 131-153 (23)
Author: Christina Roebke, Jürgen Harder and Jens E. Meyer
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There is increasing evidence that Antimicrobial Peptides (AMPs) are differentially regulated in cancers such as Oral Squamous Cell Carcinomas (OSCC). Data showing that AMPs influence the growth of tumor cells, exhibit direct cytotoxic activity towards cancer cells, function as a tumor suppressor gene or activate the adaptive immunity suggest that a dysregulation of AMPs may be associated with the development of cancer. There is no question that, with increasing resistance against conventional chemotherapy, novel anticancer agents are needed. It is interesting to speculate that natural AMP or synthetic derivatives can be used to develop novel strategies to fight cancer diseases and may represent a novel family of anticancer agents. However, future research is needed to employ the role of AMPs in cancer and to investigate their role as potential anticancer drugs.
Inhibiting Cell Cycle Kinases in Cancer Therapy
Page: 154-188 (35)
Author: Guillermo de Cárcer, Ignacio Pérez de Castro and Marcos Malumbres
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Many tumor-associated mutations result in the abnormal regulation of protein kinases involved in the progression throughout the cell division cycle. The cyclin-dependent kinase (CDK) family has received special attention due to their function as sensors of the mitogenic signals and their central role in cell proliferation. These kinases are frequently upregulated in human cancer most frequently due to overexpression of their cyclin partners or inactivation of the CDK inhibitors. A plethora of small-molecule CDK inhibitors have been characterized in the last years and some of them are currently under clinical development. Other serine-threonine protein kinases such as the Aurora proteins (mostly Aurora A and B) or Polo-like kinases (PLK1) are receiving increased attention as putative cancer targets. Other less studied mitotic kinases such TTK (MPS1), BUB and NEK proteins might also be relevant candidates as new targets of interest in cancer therapy since they play relevant roles on mitotic progression and the spindle checkpoint. Although targeting cell cycle kinases is an efficient procedure to arrest cell proliferation, the best strategy to potently and specifically inhibit tumor cell proliferation is not obvious yet. Thus, cell cycle kinases may be of interest as targets to abrogate checkpoints and favor apoptotic cell death in tumor cells. New biochemical and genetic studies are required to clarify the use of these kinases as targets in new opportunities to improve cancer therapy.
mTOR Inhibitors (Rapamycin and Its Derivatives) and Nitrogen Containing Bisphosphonates: Bi-functional Compounds for the Treatment of Bone Tumours
Page: 189-202 (14)
Author: Ory Benjamin, Moriceau Gatien, Gobin Bérengère, Redini Françoise and Heymann Dominique
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N-BP, rapamycin and its derivatives have been originally developed respectively as anti-resorptive and anti-fungal agents. In fact, in vitro and in vivo experiments demonstrated that these compounds are multi-functional molecules exerting their effects on tumour cell growth and bone remodelling. The major challenge in treating cancer relates to mutations in key genes such as p53, Rb or proteins affecting caspase signalling carried by many tumour cells. Whether nitrogen containing bisphosphonates (N-BP) are potent bone inhibitors, they also inhibit tumour cell proliferation and increase atypical apoptosis of bone tumour cells regardless of the p53 and Rb status. N-BP may be then considered as effective therapeutic agents in clinical trials of bone tumours. Rapamycin and its derivatives inhibit mTOR dependent mRNA translation both in osteoclasts and tumour cells. Cellular physiological mechanisms regulated by mTOR integrate many environmental parameters including growth factors, hormones, cytokines, amino acids, energy availability and cellular stresses that are coupled with cell cycle progression and cell growth. Rapamycin and its derivatives as well as N-BP must be considered as bi-(multi) functional molecules affecting simultaneously bone and tumour metabolisms. The present survey describes these two molecular families and discusses their therapeutic interests for primary bone tumours and bone metastases.
New Biological Approaches in Asthma: DNA-Based Therapy
Page: 203-226 (24)
Author: Li-Chieh Wang, Jyh-Hong Lee, Yao-Hsu Yang, Yu-Tsan Lin and Bor-Luen Chiang
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Asthma is characterized by airway inflammation, bronchial hyperresponsiveness, and reversible airway obstruction. Medications for asthma include corticosteroids, β2-adrenergic receptor agonists, chromones, methylxanthines, and leukotriene modifiers. Despite these advances in therapy, many symptoms are not well controlled. Since asthma is a chronic airway inflammation with a bias towards a type 2 T helper (Th2) cell response, some new approaches are targeted towards the Th2 inflammation pathway. These include anti-IgE therapy, anti-Th2 cytokine therapy, and therapies aiming at increasing Th1 cytokines. This article will focus on DNA-based therapy, a novel therapeutic strategy for asthma. Immunostimulatory gene therapy using CpG oligodeoxynucleotides with central deoxycytidyldeoxyguanosine (CpG) dinucleotide, in which the cytosine nucleobase is unmethylated, can stimulate the innate immunity and augment Th1 response. With DNA gene therapy, genes can be introduced to target Th1 cytokines or other mediators in the airway in order to counteract Th2 inflammation in asthma. Also, antisense oligonucleotides can target mRNA species of interest in asthma. Through these therapies, we can expect long-lasting effects, better control of symptoms, and reducing medication in the future.
Building a Bridge Between Clinical and Basic Research: the Phenotypic Elements of Familial Predisposition to Type 1 Diabetes
Page: 227-248 (22)
Author: Elena Matteucci and Ottavio Giampietro
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Familial aggregation has been shown for type 1 diabetes (T1D) although the nature of the factors (environment and/or genetics) responsible remains unclear. Familial clustering of diabetic nephropathy as well as of increased cardiovascular morbidity and early mortality has also been observed.
This review describes the nearly 20 years history of our investigation in parallel with contemporary literature. The story is presented from the early years’ strong focus on possible markers of T1D nephropathy (urinary albumin, urinary enzymes, erythrocyte Na/Li countertransport, and erythrocyte Na/H exchange) to the last clinical investigations to determine relevant biological markers of familial predisposition to T1D. Our studies of case-families recruited unaffected firstdegree relatives of sporadic T1D cases and population-based controls. Unlike multiple-case families, these families are those less likely to carry a strong genetic predisposition. Participants were both interviewed and provided biological material for a detailed functional characterisation of their biochemical phenotype. These studies have initially excluded that the erythrocyte Na/H exchange could be a marker of diabetic nephropathy. On the contrary, NHE activity was significantly higher in T1D family members independently of the presence of renal disease. Basic science knowledge of NHE and its functional implications have also been reviewed. Unexpectedly, we found evidence of increased oxidative stress in nondiabetic normotensive relatives of T1D patients, apart from soluble markers of autoimmunity and despite seemingly intact antioxidant defences. Markers of oxidation were associated with markers of inflammation and we concluded that the familial increase in NHE activity could be ascribed to the direct stimulatory effect of oxidative stress.
Relatives showed also immunological hallmarks and cardiovascular abnormalities that were related to indices of oxidative stress and metabolic syndrome. Other peculiarities emerged from measuring the erythrocytes redox system that exports electrons across the cell membrane to external oxidants as a function of cytoplasmic electron donor concentration. This electron transfer might reflect the functional state of membrane proton pumps that modulate intracellular redox levels. The transport system contributed to oxidation in T1D families, whereas in healthy people it protected from oxidation. Furthermore, dietary intake of vitamin C and sporting activities modulated erythrocyte electron transfer efficiency.
The contribution of environmental factors was investigated using the European Prospective Investigation of Cancer and Nutrition questionnaires that provided evidence of common unhealthy dietary behaviours, which could even predispose to the development of diabetes and cardiovascular complications, in subjects living in Pisa. However, lifestyle of T1D relatives was indistinguishable from those of controls, except for the higher daily intake of niacin and the lower physical activity levels. No difference in smoking or alcohol consumption emerged among families and controls.
The oxidative stress is a non-specific though certain component of pathogenesis at numerous diseases states of aerobic organisms. Although molecular genetic analysis has produced significant progress in T1D phenotype, much remains to be learned about the molecular sequence of events leading from a generic familial pro-oxidant background to a sporadic form of T1D (where oxidative damage targets the insulin-secreting cells).
Molecular Lipophilicity in Protein Modeling and Drug Design
Page: 249-290 (42)
Author: Roman G. Efremov, Anton O. Chugunov, Timothy V. Pyrkov, John P. Priestle, Vladimir M. Pentkovsky, Alexander S. Arseniev and Edgar Jacoby
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Hydrophobic interactions play a key role in the folding and maintenance of the 3-dimensional structure of proteins, as well as in the binding of ligands (e.g., drugs) to protein targets. Therefore, quantitative assessment of spatial hydrophobic (lipophilic) properties of these molecules is indispensable for the development of efficient computational methods in drug design. One possible solution to the problem lies in application of a concept of the 3-dimensional molecular hydrophobicity potential (MHP). The formalism of MHP utilizes a set of atomic physicochemical parameters evaluated from octanol-water partition coefficients (log P) of numerous chemical compounds. It permits detailed assessment of the hydrophobic and/or hydrophilic properties of various parts of molecules and may be useful in analysis of protein-protein and protein-ligand interactions.
This review surveys recent applications of MHP–based techniques to a number of biologically relevant tasks. Among them are: (i) Detailed assessment of hydrophobic/hydrophilic organization of proteins; (ii) Application of this data to the modeling of structure, dynamics, and function of globular and membrane proteins, membrane-active peptides, etc. (iii) Employment of the MHP-based criteria in docking simulations for ligands binding to receptors.
It is demonstrated that the application of the MHP-based techniques in combination with other molecular modeling tools (e.g., Monte Carlo and molecular dynamics simulations, docking, etc.) permits significant improvement to the standard computational approaches, provides additional important insights into the intimate molecular mechanisms driving protein assembling in water and in biological membranes, and helps in the computer-aided drug discovery process.
Hydrogen/Deuterium Exchange-Mass Spectrometry: A Powerful Tool for Probing Protein Structure, Dynamics and Interactions
Page: 291-323 (33)
Author: Yuko Tsutsui and Patrick L. Wintrode
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Knowledge of the structure and dynamics of proteins and protein assemblies is critical both for understanding the molecular basis of physiological and patho-physiological processes and for guiding drug design. While X-ray crystallography and nuclear magnetic resonance spectroscopy are both excellent techniques for this purpose, both suffer from limitations, including the requirement for high quality crystals and large amounts of material. Recently, hydrogen/ deuterium exchange measured using mass spectrometry (HXMS) has emerged as a powerful new tool for the study of protein structure, dynamics and interactions in solution. HXMS exploits the fact that backbone amide hydrogens can exchange with deuterium when a protein is incubated in D2O, and that the rate of the exchange process is highly dependent on the local structural environment. Several features of HXMS make it an especially attractive approach, including small sample requirements and the ability to study extremely large protein assemblies that are not amenable to other techniques. Here, we provide an overview of HXMS and describe several recent applications to problems of medical interest. After reviewing the molecular basis of the H/D exchange process, the different steps of the HXMS experiment – labeling, rapid proteolysis, fragment separation and mass measurement – are described, followed by a discussion of data analysis methods. Finally, we describe recent results on the application of HXMS to 1) mapping drug/inhibitor binding sites and detecting drug induced conformational changes, 2) studying viral capsid structure and assembly, and 3) characterizing the structure of pathological protein conformations, specifically amyloid fibrils.
From Drug Target to Leads-Sketching a Physico-Chemical Pathway for Lead Molecule Design In Silico
Page: 324-360 (37)
Author: Saher Afshan Shaikh, Tarun Jain, Gurvisha Sandhu, Anjali Soni and Bhyravabhotla Jayaram
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The discovery of new pharmaceuticals via computer modeling is one of the key challenges in modern medicine. The advent of global networks of genomic, proteomic and metabolomic endeavors is ushering in an increasing number of novel and clinically important targets for screening. Computational methods are anticipated to play a pivotal role in exploiting the structural and functional information to understand specific molecular recognition events of the target macromolecule with candidate hits leading ultimately to the design of improved leads for the target. In this review, we sketch a system independent, comprehensive physicochemical pathway for lead molecule design focusing on the emerging in silico trends and techniques. We survey strategies for the generation of candidate molecules, docking them with the target and ranking them based on binding affinities. We present a molecular level treatment for distinguishing affinity from specificity of a ligand for a given target. We also discuss some significant aspects of drug absorption, distribution, metabolism, excretion and toxicity (ADMET) and highlight improved protocols required for higher quality and throughput of in silico methods employed at early stages of discovery. We present a realization of the various stages in the pathway proposed with select examples from the literature and from our own research to demonstrate the way in which an iterative process of computer design and validation can aid in developing potent leads. The review thus summarizes recent advances and presents a viewpoint on improvements envisioned in the years to come for automated computer aided lead molecule discovery.
Bis and Tris Indole Alkaloids from Marine Organisms: New Leads for Drug Discovery
Page: 361-385 (25)
Author: Leena Gupta, Archna Talwar and P. M. S. Chauhan
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The marine organisms are a rich source of varied natural products with unique functionality. Marine natural products chemistry has undergone an explosive growth during the past three decades. A variety of natural products of new molecular structures with diverse biological activities have been reported from marine flora and fauna, thus ensuring for us motivation in the search of newer natural products. The bis and trisindole alkaloids are a class of marine natural products that show unique promise in the development of new drug leads.3-hydroxy staurosporine 51, an indolo carbazole having powerful antiproliferative activity. Hamacanthin A 1 and B 2, pyrazinone alkaloids have significant antimicrobial activity. Coscinamides 60-62 and Chondriamides 63-65 an indolic enamides which have anti-HIV and cytotoxic activity respectively. Gelluisine A 66 and B 67, trisindole alkaloids have strong anti-serotonin activity and strong affinity with somatostatin and neuropeptide Y receptors in receptor-binding assays. This report reviews the literature on these alkaloids from marine origin and highlights the isolation, structure, latest synthesis and specific biological activities include: cytotoxicity, antiviral, antiparasitic, serotonin antagonism and other pharmacological activities of sixty-nine bis and trisindole alkaloids.
Derivatives of Nucleic Acids for Selective RNA Targeting
Page: 386-411 (26)
Author: Vaijayanti A. Kumar
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The synthesis of backbone-modified nucleic acids has been an area of very intense research over the last two decades. The main reason for this research activity being the instability of nucleic acid based drugs in the intracellular conditions. The changes in the sugar-phosphate backbone invariably bring about the changes in the complementation properties of the nucleic acids. The naturally occurring deoxyribose- (DNA) and ribose (RNA) sugar-phosphate backbones are endowed with considerable differences in their binding affinities towards themselves. This occurs because of the different sugar conformations prevalent in DNA and RNA and the subtle structural changes accruing from these in hydrogen bonding, base stacking interactions and hydration of major/minor groves. The sixatom phosphodiester linkages and pentose-sugars give immense opportunities for chemical modifications that lead to several backbone-modified nucleic acid structures. This article is focused on such modifications that impart RNA-selective binding properties to the modified nucleic acid mimics and the rationale behind the said selectivity. It is found that the six-atom sugar-phosphate backbone could be replaced by either one-atom extended or one-atom edited repeating units, leading to the folded or extended geometries to maintain the internucleoside distancecomplementarity. Other important contributions come from electronegativity of the substituent groups, hydration in the major/minor grove, base stacking etc.
Poly(ADP-ribose) Polymerase Inhibitors: New Pharmacological Functions and Potential Clinical Implications
Page: 412-471 (60)
Author: Catalina Alarcón de la Lastra, Isabel Villegas Lama and Marina Sánchez-Fidalgo
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Poly(ADP-ribose) polymerase (PARP) comprises of a family of enzymes which catalyses poly(ADP-ribosyl)ation of DNA-binding proteins. To date, 17 isoforms of PARP with different structural domains and functions have been identified: PARP-1, PARP-2, PARP-3, PARP-4 (Vault-PARP), PARP-5 (Tankyrases-1 and 2), PARP-6, PARP-7 (tiPARP), PARP-8, PARP-9 (BAL1), PARP-10, PARP-11, PARP-12, PARP-13 (ZAP), PARP-14 (CoaSt6), PARP-15, and PARP-16. PARP-1, the best characterised member, works as a DNA damage nick-sensor protein that uses beta-NAD+ to form polymers of ADP-ribose and has been implicated in DNA repair, maintenance of genomic integrity and mammalian longevity. The generation of free radicals, reactive oxygen species and peroxynitrite, causes overactivation of PARP resulting in the depletion of NAD+ and ATP and consequently in necrotic cell death and organ dysfunction. PARP has also been involved in the up-regulation of numerous pro-inflammatory genes through the activation of several transcription nuclear factors. Thus, PARP plays an important role in the pathogenesis of several diseases, such as, stroke, myocardial infarction, circulatory shock, diabetes, neurodegenerative disorders, including Parkinson and Alzheimer diseases, allergy, colitis and other inflammatory disorders. Pharmacological modulation of PARP activity may constitute a suitable target to enhance the cytotoxicity of certain DNA-damaging anticancer drugs. Also, PARP inhibition may be a viable strategy to control viral infections. This review is intended to provide an appreciation of new pharmacological perspectives of these remarkable drugs, summarize novel underlying mechanisms and discuss their potential clinical implications.
“Frontiers in Medicinal Chemistry” is an Ebook series devoted to the review of areas of important topical interest to medicinal chemists and others in allied disciplines. “Frontiers in Medicinal Chemistry” covers all the areas of medicinal chemistry, including developments in rational drug design, bioorganic chemistry, high-throughput screening, combinatorial chemistry, compound diversity measurements, drug absorption, drug distribution, metabolism, new and emerging drug targets, natural products, pharmacogenomics, chemoinformatics, and structure-activity relationships. Medicinal chemistry as a discipline is rapidly maturing. The study of how structure and function are related is absolutely essential to understanding the molecular basis of life. “Frontiers in Medicinal Chemistry” aims to contribute in a major way to the growth of scientific knowledge and insight, and facilitate the discovery and development of new therapeutic agents to treat debilitating human disorders. This Ebook series is essential for any medicinal chemist who wishes to be kept informed and up-to-date with the latest and the most important advances.