Chanalaris Anastasios, Doherty Christine, Marsden Brian D, Bambridge Gabriel, Wren Stephen P, Nagase Hideaki, Troeberg Linda
Arthritis Research UK Centre for Osteoarthritis Pathogenesis, Kennedy Institute of Rheumatology, (A.C., C.D., G.B., H.N., L.T.), Structural Genomics Consortium (B.D.M.), and Alzheimer's Research UK Oxford Drug Discovery Institute (S.P.W.), University of Oxford, Oxford, United Kingdom.
Arthritis Research UK Centre for Osteoarthritis Pathogenesis, Kennedy Institute of Rheumatology, (A.C., C.D., G.B., H.N., L.T.), Structural Genomics Consortium (B.D.M.), and Alzheimer's Research UK Oxford Drug Discovery Institute (S.P.W.), University of Oxford, Oxford, United Kingdom
Mol Pharmacol. 2017 Oct;92(4):459-468. doi: 10.1124/mol.117.109397. Epub 2017 Aug 10.
Osteoarthritis is a common degenerative joint disease for which no disease-modifying drugs are currently available. Attempts to treat the disease with small molecule inhibitors of the metalloproteinases that degrade the cartilage matrix have been hampered by a lack of specificity. We aimed to inhibit cartilage degradation by augmenting levels of the endogenous metalloproteinase inhibitor, tissue inhibitor of metalloproteinases (TIMP)-3, through blocking its interaction with the endocytic scavenger receptor, low-density lipoprotein receptor-related protein 1 (LRP1). We discovered that suramin (CHNOS) bound to TIMP-3 with a value of 1.9 ± 0.2 nM and inhibited its endocytosis via LRP1, thus increasing extracellular levels of TIMP-3 and inhibiting cartilage degradation by the TIMP-3 target enzyme, adamalysin-like metalloproteinase with thrombospondin motifs 5. NF279 (8,8'-[carbonyl(imino-4,1-phenylenecarbonylimino-4,1-phenylenecarbonylimino)]-1,3,5-naphthalenetrisulfonic acid hexasodium salt), a structural analog of suramin, has an increased affinity for TIMP-3 and increased ability to inhibit TIMP-3 endocytosis and protect cartilage. Suramin is thus a promising scaffold for the development of novel therapeutics to increase TIMP-3 levels and inhibit cartilage degradation in osteoarthritis.
骨关节炎是一种常见的退行性关节疾病，目前尚无改善病情的药物。试图用降解软骨基质的金属蛋白酶小分子抑制剂来治疗该疾病，却因缺乏特异性而受阻。我们旨在通过阻断内源性金属蛋白酶抑制剂——金属蛋白酶组织抑制剂（TIMP）-3与内吞清道夫受体——低密度脂蛋白受体相关蛋白1（LRP1）的相互作用，来提高TIMP-3的水平，从而抑制软骨降解。我们发现，苏拉明（CHNOS）与TIMP-3结合，解离常数为1.9±0.2 nM，并通过LRP1抑制其胞吞作用，从而提高TIMP-3的细胞外水平，并通过TIMP-3的靶酶——含血小板反应蛋白基序的解聚素样金属蛋白酶5抑制软骨降解。苏拉明的结构类似物NF279（8,8'-[羰基（亚氨基-4,1-亚苯基羰基亚氨基-4,1-亚苯基羰基亚氨基）]-1,3,5-萘三磺酸六钠盐）对TIMP-3的亲和力增加，抑制TIMP-3胞吞作用和保护软骨的能力增强。因此，苏拉明是开发新型疗法以提高TIMP-3水平并抑制骨关节炎中软骨降解的一个有前景的支架。
