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
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
Current advances in inherited cardiomyopathy
Describe in detail all novel advances in multimodality imaging related to inherited cardiomyopathy diagnosis and prognosis. Shed light to deeper phenotypic characterization. Acknowledge recent advances in genetics, genomics and precision medicineread 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
-
Receptor for AGEs (RAGE) as Mediator of NF-kB Pathway Activation in Neuroinflammation and Oxidative Stress
CNS & Neurological Disorders - Drug Targets Acute Kidney Injury: Turning the Tide
Current Drug Targets Restoring the Dysfunctional Endothelium
Current Pharmaceutical Design Perinatal Asphyxia in Preterm Neonates Leads to Serum Changes in Protein S-100 and Neuron Specific Enolase
Current Neurovascular Research New Challenges and Strategies for Cardiac Disease: Autophagy, mTOR, and AMP-activated Protein Kinase
Current Neurovascular Research The Serpin Solution; Targeting Thrombotic and Thrombolytic Serine Proteases in Inflammation
Cardiovascular & Hematological Disorders-Drug Targets Detrimental Effects of Hyperglycemia in Acute Coronary Syndromes: from Pathophysiological Mechanisms to Therapeutic Strategies
Mini-Reviews in Medicinal Chemistry Atheroma Burden and Morphology in Women
Current Pharmaceutical Design Endogenous Agmatine Inhibits Cerebral Vascular Matrix Metalloproteinases Expression by Regulating Activating Transcription Factor 3 and Endothelial Nitric Oxide Synthesis
Current Neurovascular Research Targeting Mitochondria for Cardiac Protection
Current Drug Targets Modulation of Neuro-Inflammation and Vascular Response by Oxidative Stress Following Cerebral Ischemia-Reperfusion Injury
Current Medicinal Chemistry Histone Deacetylase Inhibitors Target Diabetes via Chromatin Remodeling or as Chemical Chaperones?
Current Diabetes Reviews Pro- and Anti-Arrhythmic Effects of Anti-Inflammatory Drugs
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry Use of Fullerenes in Cosmetics
Recent Patents on Biotechnology Therapeutic Approach for Neuronal Disease by Regulating Reninangiotensin System
Current Hypertension Reviews Exploring New CGRP Family Peptides and their Receptors in Vertebrates
Current Protein & Peptide Science Techniques to Investigate Neuronal Mitochondrial Function and its Pharmacological Modulation
Current Drug Targets Mesenchymal Stem Cells: A Good Candidate for Restenosis Therapy?
Current Vascular Pharmacology Role of Endogenous Granulocyte-Macrophage Colony Stimulating Factor Following Stroke and Relationship to Neurological Outcome
Current Neurovascular Research Nanotechnology Based Diagnostic and Therapeutic Strategies for Neuroscience with Special Emphasis on Ischemic Stroke
Current Medicinal Chemistry