Exosite inhibition of ADAMTS-5 by a glycoconjugated arylsulfonamide

Abstract 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....

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Autores principales:	Salvatore Santamaria, Doretta Cuffaro, Elisa Nuti, Lidia Ciccone, Tiziano Tuccinardi, Francesca Liva, Felicia D’Andrea, Rens de Groot, Armando Rossello, Josefin Ahnström
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/56c563a9e37d4463930edc6fb1a77ba9
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spelling	oai:doaj.org-article:56c563a9e37d4463930edc6fb1a77ba92021-12-02T14:12:46ZExosite inhibition of ADAMTS-5 by a glycoconjugated arylsulfonamide10.1038/s41598-020-80294-12045-2322https://doaj.org/article/56c563a9e37d4463930edc6fb1a77ba92021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-80294-1https://doaj.org/toc/2045-2322Abstract 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 β-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.Salvatore SantamariaDoretta CuffaroElisa NutiLidia CicconeTiziano TuccinardiFrancesca LivaFelicia D’AndreaRens de GrootArmando RosselloJosefin AhnströmNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Salvatore Santamaria Doretta Cuffaro Elisa Nuti Lidia Ciccone Tiziano Tuccinardi Francesca Liva Felicia D’Andrea Rens de Groot Armando Rossello Josefin Ahnström Exosite inhibition of ADAMTS-5 by a glycoconjugated arylsulfonamide
description	Abstract 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 β-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.
format	article
author	Salvatore Santamaria Doretta Cuffaro Elisa Nuti Lidia Ciccone Tiziano Tuccinardi Francesca Liva Felicia D’Andrea Rens de Groot Armando Rossello Josefin Ahnström
author_facet	Salvatore Santamaria Doretta Cuffaro Elisa Nuti Lidia Ciccone Tiziano Tuccinardi Francesca Liva Felicia D’Andrea Rens de Groot Armando Rossello Josefin Ahnström
author_sort	Salvatore Santamaria
title	Exosite inhibition of ADAMTS-5 by a glycoconjugated arylsulfonamide
title_short	Exosite inhibition of ADAMTS-5 by a glycoconjugated arylsulfonamide
title_full	Exosite inhibition of ADAMTS-5 by a glycoconjugated arylsulfonamide
title_fullStr	Exosite inhibition of ADAMTS-5 by a glycoconjugated arylsulfonamide
title_full_unstemmed	Exosite inhibition of ADAMTS-5 by a glycoconjugated arylsulfonamide
title_sort	exosite inhibition of adamts-5 by a glycoconjugated arylsulfonamide
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/56c563a9e37d4463930edc6fb1a77ba9
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Exosite inhibition of ADAMTS-5 by a glycoconjugated arylsulfonamide

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