Related Experiment Videos
Poly(ADP-ribose)polymerase inhibition - where now?
Esther C Y Woon1, Michael D Threadgill
1Department of Pharmaceutical Chemistry, School of Phatmacy, University of London, UK.
Current Medicinal Chemistry
|September 27, 2005
Summary
Poly(ADP-ribose)polymerase (PARP) inhibitors show promise for treating various diseases, but challenges remain in their development. Key questions involve improving water-solubility, achieving tissue selectivity, understanding chronic inhibition effects, and exploring isoform selectivity for PARP-1 inhibitors.
Area of Science:
- Biochemistry
- Pharmacology
- Molecular Biology
Background:
- Poly(ADP-ribose)polymerases (PARPs) synthesize poly(ADP-ribose) polymers from NAD(+).
- PARP-1 inhibitors have been investigated for over 25 years for various diseases, with recent entry into clinical trials.
- Current inhibitors primarily mimic NAD(+) and target the catalytic site, with structure-activity relationships understood.
Purpose of the Study:
- To address five critical questions hindering the full therapeutic potential of PARP-1 inhibitors.
- To explore strategies for enhancing water-solubility and tissue selectivity of PARP-1 inhibitors.
- To investigate the implications of chronic PARP-1 inhibition and the necessity of isoform selectivity.
Main Methods:
- Review of existing literature on PARP-1 inhibitor design and structure-activity relationships.
- Analysis of challenges related to pharmacophore properties, such as water-solubility.
- Consideration of prodrug approaches for tissue selectivity and long-term vs. short-term inhibition strategies.
Main Results:
- The consensus PARP-1 inhibitor pharmacophore presents a challenge for water-solubility.
- Tissue-selective inhibition may be achievable through prodrug strategies.
- Potential issues associated with chronic inhibition of DNA repair processes require further investigation.
- The necessity and feasibility of isoform-selective PARP-1 inhibition remain open questions.
- Inhibition of poly(ADP-ribose)-glycohydrolase (PARG) is presented as an alternative therapeutic strategy.
Conclusions:
- Addressing water-solubility, tissue selectivity, and chronic inhibition challenges is crucial for PARP-1 inhibitor development.
- The role of isoform selectivity for PARP-1 inhibitors needs further clarification.
- Exploring alternative targets like PARG may offer new therapeutic avenues for diseases involving PARP activity.