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Targeting Aggrecanases for Osteoarthritis Therapy: From Zinc Chelation to Exosite Inhibition
Doretta Cuffaro1, Lidia Ciccone1, Armando Rossello1
1Department of Pharmacy, University of Pisa, via Bonanno 6, 56126 Pisa, Italy.
Abstract:
Osteoarthritis (OA) is the most common degenerative joint disease. In 1999, two members of the A Disintegrin and Metalloproteinase with Thrombospondin Motifs (ADAMTS) family of metalloproteinases, ADAMTS4 and ADAMTS5, or aggrecanases, were identified as the enzymes responsible for aggrecan degradation in cartilage. The first aggrecanase inhibitors targeted the active site by chelation of the catalytic zinc ion. Due to the generally disappointing performance of zinc-chelating inhibitors in preclinical and clinical studies, inhibition strategies tried to move away from the active-site zinc in order to improve selectivity. Exosite inhibitors bind to proteoglycan-binding residues present on the aggrecanase ancillary domains (called exosites). While exosite inhibitors are generally more selective than zinc-chelating inhibitors, they are still far from fulfilling their potential, partly due to a lack of structural and functional data on aggrecanase exosites. Filling this gap will inform the design of novel potent, selective aggrecanase inhibitors.
Insights
Osteoarthritis (OA) is a common joint disease. New research focuses on aggrecanase exosites to develop better inhibitors for cartilage degradation, moving beyond less effective zinc-targeting drugs.
Area of Science:
- Biochemistry
- Biomedical Engineering
- Molecular Biology
Background:
- Osteoarthritis (OA) is the most prevalent degenerative joint disease.
- ADAMTS4 and ADAMTS5 (aggrecanases) degrade cartilage aggrecan.
- Previous inhibitors targeting the catalytic zinc ion showed limited success.
Purpose of the Study:
- To explore novel strategies for aggrecanase inhibition.
- To address the limitations of current zinc-chelating inhibitors.
- To investigate the potential of exosite inhibitors for improved selectivity.
Main Methods:
- Review of existing literature on aggrecanase inhibitors.
- Analysis of the structural and functional data of aggrecanase exosites.
- Exploration of exosite-targeting inhibition strategies.
Main Results:
- Exosite inhibitors offer greater selectivity than zinc-chelating inhibitors.
- A lack of structural and functional data on aggrecanase exosites hinders inhibitor development.
- Targeting exosites is a promising strategy for potent and selective aggrecanase inhibition.
Conclusions:
- Further research into aggrecanase exosites is crucial.
- Understanding exosites will enable the design of next-generation OA therapeutics.
- Developing novel aggrecanase inhibitors can significantly impact OA treatment.
