ArticleScientific reports2021
Exosite inhibition of ADAMTS-5 by a glycoconjugated arylsulfonamide.
Article in Scientific reports, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 24 citations in OpenAlex.
- ADAM and ADAMTS proteases as integrative hubs in heart failure pathogenesis and therapy.iScience · 2026Review
- Bridging the gap in OA therapeutics: Bioengineered strategies to target osteoclast-chondrocyte crosstalk.Bioengineering & translational medicine · 2026Review
- Computational Insights into Flavonoids for ADAMTS-5 Exosite Inhibition in Knee Osteoarthritis: Docking, MD Simulations, and Machine Learning-Guided Structure Prediction.Molecules (Basel, Switzerland) · 2026Article
- Molecular Dynamics Simulations with NAMD and Trajectory Analysis.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Design, synthesis and biological activity of glycoconjugated ADAMTS5 exosite inhibitors: applications in osteoarthritis and ovarian cancer models.Scientific reports · 2025Article
- Article
- The protease ADAMTS5 controls ovarian cancer cell invasion, downstream of Rab25.The FEBS journal · 2025Article
- In Silico Insights into the Inhibition of ADAMTS-5 by Punicalagin and Ellagic Acid for the Treatment of Osteoarthritis.International journal of molecular sciences · 2025Article
- Exploring Placental Protein-Target Protein Interactions:Current protein & peptide science · 2025Article
- Regulation of Peptidase Activity beyond the Active Site in Human Health and Disease.International journal of molecular sciences · 2023Review
- Targeting Aggrecanases for Osteoarthritis Therapy: From Zinc Chelation to Exosite Inhibition.Journal of medicinal chemistry · 2022Review
- The Mechanism and Role of ADAMTS Protein Family in Osteoarthritis.Biomolecules · 2022Review
- Osteoarthritis Pathophysiology: Therapeutic Target Discovery may Require a Multifaceted Approach.Clinics in geriatric medicine · 2022Review
- ADAM and ADAMTS disintegrin and metalloproteinases as major factors and molecular targets in vascular malfunction and disease.Advances in pharmacology (San Diego, Calif.) · 2022Article
- Identification of novel ADAMTS1, ADAMTS4 and ADAMTS5 cleavage sites in versican using a label-free quantitative proteomics approach.Journal of proteomics · 2021Article
- Targeting Cartilage Degradation in Osteoarthritis.Pharmaceuticals (Basel, Switzerland) · 2021Review
- Regulation of ADAMTS Proteases.Frontiers in molecular biosciences · 2021Review
- Extracellular Matrix Enzymes and Immune Cell Biology.Frontiers in molecular biosciences · 2021Review
- ADAMTS5 in Osteoarthritis: Biological Functions, Regulatory Network, and Potential Targeting Therapies.Frontiers in molecular biosciences · 2021Review
- Targeting the Host Response: Can We Manipulate Extracellular Matrix Metalloproteinase Activity to Improve Influenza Virus Infection Outcomes?Frontiers in molecular biosciences · 2021Review
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.