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Exosite inhibition of A Disintegrin And Metalloproteinase with Thrombospondin motif (ADAMTS)-5 by a glycoconjugated arylsulfonamide

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Santamaria et al. SciRep 2020.pdfWorking paper1.09 MBAdobe PDFView/Open
Title: Exosite inhibition of A Disintegrin And Metalloproteinase with Thrombospondin motif (ADAMTS)-5 by a glycoconjugated arylsulfonamide
Authors: Salvatore, S
Cuffaro, D
Nuti, E
Ciccone, L
Tuccinardi, T
Liva, F
D’Andrea, F
De Groot, R
Rossello, A
Ahnström, J
Item Type: Working Paper
Abstract: ADAMTS-5 is a major protease involved in the turnover of proteoglycans such as aggrecan and versican. Its aggrecanase activity has been directly linked to the etiology of osteoarthritis (OA), identifying ADAMTS-5 as a pharmaceutical target for OA treatment. However, most existing ADAMTS-5 inhibitors target its active site and therefore suffer from poor selectivity. Here, using a novel approach, we have designed a new class of sugar-based arylsulfonamide inhibitors, which are selective for ADAMTS-5 through binding to a previously unknown substrate-binding site (exosite). Docking calculations combined with molecular dynamics simulations demonstrated that our lead compound is a cross-domain inhibitor that targets the interface of the metalloproteinase and disintegrin-like domains. Targeted mutagenesis identified disintegrin-like domain residues K532 and K533 as an exosite which is critical for substrate recognition. Furthermore, we show that this exosite acts as major determinant for inhibitor binding and, therefore, can be targeted for development of selective ADAMTS-5 inhibitors.
Issue Date: 12-Jun-2020
URI: http://hdl.handle.net/10044/1/85363
DOI: 10.1101/2020.06.12.146324
Publisher: Cold Spring Harbor Laboratory
Copyright Statement: © 2020 The Author(s).
Sponsor/Funder: British Heart Foundation
Funder's Grant Number: PG/18/15/33566
Appears in Collections:Department of Immunology and Inflammation