2. Academic Validation
  3. Design, synthesis and biological activity of glycoconjugated ADAMTS5 exosite inhibitors: applications in osteoarthritis and ovarian cancer models

Design, synthesis and biological activity of glycoconjugated ADAMTS5 exosite inhibitors: applications in osteoarthritis and ovarian cancer models

  • Sci Rep. 2025 Dec 11;16(1):329. doi: 10.1038/s41598-025-29549-3.
Doretta Cuffaro 1,  Sophie Blagg 2,  Kazuhiro Yamamoto 3 4,  Luca Pinzi 5,  Rachele Bacchetti 6,  Shengnan Yuan 6,  Simon Tew 3,  Paola Campagnolo 7 8,  Felicia D'Andrea 1,  Enrico Crispino 1,  Giulio Rastelli 5,  Armando Rossello 1,  Elena Rainero 6,  Elisa Nuti 9,  Salvatore Santamaria 10 11
Affiliations

Affiliations

  • 1 Department of Pharmacy, University of Pisa, Via Bonanno 6, Pisa, 56126, Italy.
  • 2 Department of Immunology and Inflammation, Imperial College London, Du Cane Road, London, W12 0NN, UK.
  • 3 Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, L7 8TX, UK.
  • 4 Scleroprotein and Leather Research Institute, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwaicho, Fuchu, 183-8509, Tokyo, Japan.
  • 5 Department of Life Sciences, University of Modena and Reggio Emilia, Via Giuseppe Campi, 103, Modena, 41125, Italy.
  • 6 School of Biosciences, University of Sheffield, Western Bank, Sheffield, S10 2TN, UK.
  • 7 Discipline of Clinical Sciences, School of Biosciences, University of Surrey, Guildford, GU2 7XH, Surrey, UK.
  • 8 Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Guildford, GU2 7XH, Surrey, UK.
  • 9 Department of Pharmacy, University of Pisa, Via Bonanno 6, Pisa, 56126, Italy. [email protected].
  • 10 Department of Immunology and Inflammation, Imperial College London, Du Cane Road, London, W12 0NN, UK. [email protected].
  • 11 Discipline of Clinical Sciences, School of Biosciences, University of Surrey, Guildford, GU2 7XH, Surrey, UK. [email protected].
PMID: 41381706 DOI: 10.1038/s41598-025-29549-3
Abstract

Pharmacological inhibition of the extracellular zinc metalloprotease A Disintegrin-like And Metalloprotease domain with Thrombospondin type I motifs 5 (ADAMTS5) has been proposed as a treatment for osteoarthritis (OA), a degenerative disease characterized by cartilage loss. More recently, ADAMTS5 has been implicated in ovarian Cancer (OC), due to its essential role in promoting cell migration and association with poor prognosis. ADAMTS5 major substrates are the proteoglycans aggrecan and versican, which support the structural integrity of the cartilage and the tumor microenvironment. We have recently described a non-chelating arylsulfonamide glycoconjugate, compound 4b, as a selective ADAMTS5 inhibitor, and shown its effectiveness in an OC 3D model. Here, we modified the structure of 4b to improve its biological activity. We showed that, while 4b induces cytotoxicity in several cell lines as well as in porcine and human cartilage explants, its derivative 2 was tolerated at high micromolar concentrations and effective in inhibiting aggrecan degradation in human ex vivo OA explants and reducing directional OC cell migration and pseudopod elongation. In silico analyses provided a rationale behind the different biological activities of the two compounds. These findings highlight the potential of non-chelating glycoconjugated arylsulfonamides to treat pathologies characterized by excessive ADAMTS5 activity.

Keywords

ADAMTS5; Aggrecan; Glycoconjugates; Osteoarthritis; Ovarian cancer; Versican.

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