Abstract
The poly(ADP-ribose)polymerases (PARPs) catalyse the transfer of ADP-ribose units from the substrate NAD+ to acceptor proteins, biosynthesising polyanionic poly(ADP-ribose) polymers. A major isoform, PARP-1, has been the target for design of inhibitors for over twenty-five years. Inhibitors of the activity of PARP-1 have been claimed to have applications in the treatment of many disease states, including cancer, haemorrhagic shock, cardiac infarct, stroke, diabetes, inflammation and retroviral infection, but only recently have PARP-1 inhibitors entered clinical trial. Most PARP-1 inhibitors mimic the nicotinamide of NAD+ and the structure-activity relationships are understood in terms of the structure of the catalytic site. However, five questions remain if PARP-1 inhibitors are to realise their potential in treating human diseases. Firstly, the consensus pharmacophore is a benzamide with N-H conformationally constrained anti to the carbonyl-arene bond but this is also a "pharmacophore" for insolubility in water; can water-solubility be designed into inhibitors without loss of potency? Secondly, some potential clinical applications require tissue-selective PARP-1 inhibition; is this possible through prodrug approaches? Thirdly, different diseases may require therapeutic PARP-1 inhibition to be either short-term or chronic; are there potential problems associated with chronic inhibition of this DNA-repair process? Fourthly, PARP-1 is one of at least eighteen isoforms; is isoform-selectivity essential, desirable or even possible? Fifthly, PARP activity can be inhibited in cells by inhibition of poly(ADP-ribose)glycohydrolase (PARG); will this be a viable strategy for future drug design? The answers to these questions will determine the future of disease therapy through inhibition of PARP.
Keywords: poly(adp-ribose)polymerase, parp, dna repair, solubility, prodrug, chronic, isoform, poly(adpribose), glycohydrolase
Current Medicinal Chemistry
Title: Poly(ADP-ribose)polymerase Inhibition - Where Now?
Volume: 12 Issue: 20
Author(s): Esther C. Y. Woon and Michael D. Threadgill
Affiliation:
Keywords: poly(adp-ribose)polymerase, parp, dna repair, solubility, prodrug, chronic, isoform, poly(adpribose), glycohydrolase
Abstract: The poly(ADP-ribose)polymerases (PARPs) catalyse the transfer of ADP-ribose units from the substrate NAD+ to acceptor proteins, biosynthesising polyanionic poly(ADP-ribose) polymers. A major isoform, PARP-1, has been the target for design of inhibitors for over twenty-five years. Inhibitors of the activity of PARP-1 have been claimed to have applications in the treatment of many disease states, including cancer, haemorrhagic shock, cardiac infarct, stroke, diabetes, inflammation and retroviral infection, but only recently have PARP-1 inhibitors entered clinical trial. Most PARP-1 inhibitors mimic the nicotinamide of NAD+ and the structure-activity relationships are understood in terms of the structure of the catalytic site. However, five questions remain if PARP-1 inhibitors are to realise their potential in treating human diseases. Firstly, the consensus pharmacophore is a benzamide with N-H conformationally constrained anti to the carbonyl-arene bond but this is also a "pharmacophore" for insolubility in water; can water-solubility be designed into inhibitors without loss of potency? Secondly, some potential clinical applications require tissue-selective PARP-1 inhibition; is this possible through prodrug approaches? Thirdly, different diseases may require therapeutic PARP-1 inhibition to be either short-term or chronic; are there potential problems associated with chronic inhibition of this DNA-repair process? Fourthly, PARP-1 is one of at least eighteen isoforms; is isoform-selectivity essential, desirable or even possible? Fifthly, PARP activity can be inhibited in cells by inhibition of poly(ADP-ribose)glycohydrolase (PARG); will this be a viable strategy for future drug design? The answers to these questions will determine the future of disease therapy through inhibition of PARP.
Export Options
About this article
Cite this article as:
Woon C. Y. Esther and Threadgill D. Michael, Poly(ADP-ribose)polymerase Inhibition - Where Now?, Current Medicinal Chemistry 2005; 12 (20) . https://dx.doi.org/10.2174/0929867054864778
DOI https://dx.doi.org/10.2174/0929867054864778 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Superoxide and Post-Ischemic Liver Injury: Potential Therapeutic Target for Liver Transplantation
Current Medicinal Chemistry New Insights into the Roles of NAD+-Poly(ADP-ribose) Metabolism and Poly(ADP-ribose) Glycohydrolase
Current Protein & Peptide Science Cardiac Oxidative Stress and Inflammatory Cytokines Response after Myocardial Infarction
Current Vascular Pharmacology Low-dose Tissue Plasminogen Activator is as Effective as Standard Tissue Plasminogen Activator Administration for the Treatment of Acute Ischemic Stroke
Current Neurovascular Research Functions of the Third Intracellular Loop of the Human Melanocortin-3 Receptor
Current Pharmaceutical Design Coumarins as Antioxidants
Current Medicinal Chemistry Current Understanding of Polymyxin B Applications in Bacteraemia/ Sepsis Therapy Prevention: Clinical, Pharmaceutical, Structural and Mechanistic Aspects
Anti-Infective Agents in Medicinal Chemistry Melatonin: Pharmacology, Functions and Therapeutic Benefits
Current Neuropharmacology Glucagon-Like Peptide 1 and the Cardiovascular System
Current Diabetes Reviews Postconditioning: A New Paradigm for Myocardial Protection?
Current Cardiology Reviews The Application of Mechanical Aerosol Delivery Systems in an in vitro Model of Mechanically Ventilated Neonates
Recent Patents on Drug Delivery & Formulation Flavonoids and the Brain: Evidences and Putative Mechanisms for a Protective Capacity
Current Neuropharmacology Cellular Iron Homeostasis and Therapeutic Implications of Iron Chelators in Cancer
Current Pharmaceutical Biotechnology Nitric Oxide and Dietary Factors: Part III Minerals, Vitamins and Other Dietary and Lifestyle Factors
Vascular Disease Prevention (Discontinued) Red Blood Cells as Modulators of T Cell Growth and Survival
Current Pharmaceutical Design Neuroprotection by Diazoxide in Animal Models for Cerebrovascular Disorders
Vascular Disease Prevention (Discontinued) Systemic Inflammatory Response, Bacterial Translocation and Nitric Oxide Donors
Inflammation & Allergy - Drug Targets (Discontinued) Relevance of Nutritional Antioxidants in Metabolic Syndrome, Ageing and Cancer: Potential for Therapeutic Targeting
Infectious Disorders - Drug Targets Role of Antioxidants for the Treatment of Cardiovascular Diseases: Challenges and Opportunities
Current Pharmaceutical Design Modulation of Cardiac Metabolism During Myocardial Ischemia
Current Pharmaceutical Design