期刊
SCIENTIFIC REPORTS
卷 11, 期 1, 页码 -出版社
NATURE RESEARCH
DOI: 10.1038/s41598-020-80294-1
关键词
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资金
- Imperial College European Partners Fund 2018
- British Heart Foundation [PG/18/15/33566]
- University of Pisa [PRA_2018_20]
ADAMTS-5 is a key protease involved in the turnover of proteoglycans, with dysregulated activity linked to osteoarthritis. A new class of sugar-based arylsulfonamides was designed based on ADAMTS-5's ability to bind beta-N-acetyl-D-glucosamine. The most promising compound, 4b, showed high selectivity over ADAMTS-4 as a non-zinc binding inhibitor targeting a previously unknown substrate-binding site critical for substrate recognition.
ADAMTS-5 is a major protease involved in the turnover of proteoglycans such as aggrecan and versican. Dysregulated aggrecanase activity of ADAMTS-5 has been directly linked to the etiology of osteoarthritis (OA). For this reason, ADAMTS-5 is a pharmaceutical target for the treatment of OA. ADAMTS-5 shares high structural and functional similarities with ADAMTS-4, which makes the design of selective inhibitors particularly challenging. Here we exploited the ADAMTS-5 binding capacity of beta-N-acetyl-D-glucosamine to design a new class of sugar-based arylsulfonamides. Our most promising compound, 4b, is a non-zinc binding ADAMTS-5 inhibitor which showed high selectivity over ADAMTS-4. Docking calculations combined with molecular dynamics simulations demonstrated that 4b is a cross-domain inhibitor that targets the interface of the metalloproteinase and disintegrin-like domains. Furthermore, the interaction between 4b and the ADAMTS-5 Dis domain is mediated by hydrogen bonds between the sugar moiety and two lysine residues (K532 and K533). Targeted mutagenesis of these two residues confirmed their importance both for versicanase activity and inhibitor binding. This positively-charged cluster of ADAMTS-5 represents a previously unknown substrate-binding site (exosite) which is critical for substrate recognition and can therefore be targeted for the development of selective ADAMTS-5 inhibitors.
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