Targeting Aggrecanases for Osteoarthritis Therapy: From Zinc Chelation to Exosite Inhibition.

Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE

Publication: Washington Dc : American Chemical Society
Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-

Procollagen N-Endopeptidase*/metabolism ; Osteoarthritis*/metabolism; Humans ; Aggrecans/metabolism ; ADAMTS5 Protein ; ADAMTS4 Protein ; Zinc ; Disintegrins ; ADAM Proteins/metabolism ; Thrombospondins

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.

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FS/IBSRF/20/25032 United Kingdom BHF_ British Heart Foundation

EC 3.4.24.14 (Procollagen N-Endopeptidase)
0 (Aggrecans)
EC 3.4.24.- (ADAMTS5 Protein)
EC 3.4.24.82 (ADAMTS4 Protein)
EC 3.4.99.- (aggrecanase)
J41CSQ7QDS (Zinc)
0 (Disintegrins)
EC 3.4.24.- (ADAM Proteins)
0 (Thrombospondins)

Date Created: 20221017 Date Completed: 20221028 Latest Revision: 20230919

20250114

PMC9620172

10.1021/acs.jmedchem.2c01177

36250680