دورية أكاديمية
Suramin analogues protect cartilage against osteoarthritic breakdown by increasing levels of tissue inhibitor of metalloproteinases 3 (TIMP-3) in the tissue.
| العنوان: | Suramin analogues protect cartilage against osteoarthritic breakdown by increasing levels of tissue inhibitor of metalloproteinases 3 (TIMP-3) in the tissue. |
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| المؤلفون: | Green J; Norwich Medical School, University of East Anglia, Norwich NR4 7UQ, United Kingdom., Tinson RAJ; Norwich Medical School, University of East Anglia, Norwich NR4 7UQ, United Kingdom; School of Pharmacy, University of East Anglia, Norwich NR4 7TJ, United Kingdom., Betts JHJ; Norwich Medical School, University of East Anglia, Norwich NR4 7UQ, United Kingdom., Piras M; Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, United Kingdom., Pelut A; Norwich Medical School, University of East Anglia, Norwich NR4 7UQ, United Kingdom., Steverding D; Norwich Medical School, University of East Anglia, Norwich NR4 7UQ, United Kingdom., Wren SP; Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, United Kingdom; Department of Chemical and Pharmaceutical Sciences, Kingston University, Kingston upon Thames KT1 2EE, United Kingdom., Searcey M; School of Pharmacy, University of East Anglia, Norwich NR4 7TJ, United Kingdom., Troeberg L; Norwich Medical School, University of East Anglia, Norwich NR4 7UQ, United Kingdom. Electronic address: l.troeberg@uea.ac.uk. |
| المصدر: | Bioorganic & medicinal chemistry [Bioorg Med Chem] 2023 Sep 07; Vol. 92, pp. 117424. Date of Electronic Publication: 2023 Jul 26. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Science Country of Publication: England NLM ID: 9413298 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1464-3391 (Electronic) Linking ISSN: 09680896 NLM ISO Abbreviation: Bioorg Med Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Oxford : Elsevier Science Original Publication: Oxford : New York : Pergamon Press, c1993- |
| مواضيع طبية MeSH: | Tissue Inhibitor of Metalloproteinase-3*/metabolism , Tissue Inhibitor of Metalloproteinase-3*/pharmacology , Tissue Inhibitor of Metalloproteinase-3*/therapeutic use , Osteoarthritis*/drug therapy , Osteoarthritis*/metabolism, Humans ; Suramin/pharmacology ; Suramin/metabolism ; Suramin/therapeutic use ; Cartilage/metabolism ; Metalloproteases/metabolism ; Metalloproteases/pharmacology ; Metalloproteases/therapeutic use |
| مستخلص: | Osteoarthritis is a chronic degenerative joint disease affecting millions of people worldwide, with no disease-modifying drugs currently available to treat the disease. Tissue inhibitor of metalloproteinases 3 (TIMP-3) is a potential therapeutic target in osteoarthritis because of its ability to inhibit the catabolic metalloproteinases that drive joint damage by degrading the cartilage extracellular matrix. We previously found that suramin inhibits cartilage degradation through its ability to block endocytosis and intracellular degradation of TIMP-3 by low-density lipoprotein receptor-related protein 1 (LRP1), and analysis of commercially available suramin analogues indicated the importance of the 1,3,5-trisulfonic acid substitutions on the terminal naphthalene rings for this activity. Here we describe synthesis and structure-activity relationship analysis of additional suramin analogues using ex vivo models of TIMP-3 trafficking and cartilage degradation. This showed that 1,3,6-trisulfonic acid substitution of the terminal naphthalene rings was also effective, and that the protective activity of suramin analogues depended on the presence of a rigid phenyl-containing central region, with para/para substitution of these phenyl rings being most favourable. Truncated analogues lost protective activity. The physicochemical characteristics of suramin and its analogues indicate that approaches such as intra-articular injection would be required to develop them for therapeutic use. Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.) |
| معلومات مُعتمدة: | 21776 United Kingdom VAC_ Versus Arthritis |
| فهرسة مساهمة: | Keywords: LRP1; Low-density lipoprotein receptor-related protein 1; Osteoarthritis; Suramin; TIMP-3 |
| المشرفين على المادة: | 0 (Tissue Inhibitor of Metalloproteinase-3) 6032D45BEM (Suramin) EC 3.4.- (Metalloproteases) |
| تواريخ الأحداث: | Date Created: 20230730 Date Completed: 20230821 Latest Revision: 20240214 |
| رمز التحديث: | 20240214 |
| DOI: | 10.1016/j.bmc.2023.117424 |
| PMID: | 37517101 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1464-3391 |
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| DOI: | 10.1016/j.bmc.2023.117424 |