Selective inhibition of cathepsin S elastolytic activity by exopolysaccharides from deep-sea hydrothermal bacteria

IF 10.7 1区化学 Q1 CHEMISTRY, APPLIED

Carbohydrate Polymers Pub Date : 2025-06-27 DOI:10.1016/j.carbpol.2025.123968

Alexis David , Baptiste Rigoux , Martyna Maszota-Zieleniak , Corinne Sinquin , Catherine Neau , Agata Zykwinska , Ahlame Saidi , Gilles Lalmanach , Sergey A. Samsonov , Sylvia Colliec-Jouault , Fabien Lecaille

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Abstract

Human cathepsin S (CatS) constitutes a key orchestrator of extracellular matrix (ECM) remodeling. Recent evidence suggest that CatS inhibition is a valuable therapeutic option for inflammatory diseases that are characterized by an excessive degradation of insoluble elastin, a process in which CatS contributes significantly when it is overexpressed. Here, we report novel findings that highlight the inhibition of CatS by two low-molecular weight highly sulphated exopolysaccharides (EPS), named diabolican (Dia_9-Hsulf) and infernan (Inf_19-Hsulf), derived from two marine bacterial strains Vibrio diabolicus and Alteromonas infernus, respectively. Dia_9-Hsulf and to a lesser extent Inf_19-Hsulf were selective and potent uncompetitive inhibitors of CatS (nanomolar range), which represents an unprecedented mechanism of CatS inhibition. In addition, both EPS selectively inhibited the elastolytic activity of CatS, without affecting the degradation of its other biological substrates (e.g. collagen, thyroglobulin). Combined experimental and in silico approaches provided new insights on how highly sulfated diabolican prevented the CatS elastolytic activity by hindering its elastin-binding exosite. These results evidenced EPS as promising molecules to preserve the elastin integrity during inflammatory events implying CatS.

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深海热液细菌胞外多糖对组织蛋白酶S弹性水解活性的选择性抑制

人组织蛋白酶S （CatS）是细胞外基质（ECM）重塑的关键协调者。最近的证据表明，对于以不溶性弹性蛋白过度降解为特征的炎症性疾病，cat抑制是一种有价值的治疗选择，当cat过度表达时，它在这一过程中起着重要作用。在这里，我们报告了两种低分子量高硫酸外多糖（EPS）对cat的抑制作用的新发现，这两种低分子量高硫酸外多糖分别被命名为diabolican （Dia9-Hsulf）和infernan (Inf19-Hsulf)，它们分别来自两种海洋细菌菌株diabolicus弧菌和infernus Alteromonas。Dia9-Hsulf和较小程度的Inf19-Hsulf是选择性和有效的非竞争性cat抑制剂（纳摩尔范围），这代表了一种前所未有的cat抑制机制。此外，两种EPS都选择性地抑制了cat的弹性分解活性，而不影响其其他生物底物（如胶原蛋白、甲状腺球蛋白）的降解。结合实验和计算机方法提供了新的见解，高度硫酸化的二代谢物如何通过阻碍其弹性蛋白结合的外源性物质来阻止CatS的弹性分解活性。这些结果证明，EPS是有希望在炎症事件中保持弹性蛋白完整性的分子，这意味着cat。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Carbohydrate Polymers 化学-高分子科学

CiteScore

22.40

自引率

8.00%

发文量

1286

审稿时长

47 days

期刊介绍： Carbohydrate Polymers stands as a prominent journal in the glycoscience field, dedicated to exploring and harnessing the potential of polysaccharides with applications spanning bioenergy, bioplastics, biomaterials, biorefining, chemistry, drug delivery, food, health, nanotechnology, packaging, paper, pharmaceuticals, medicine, oil recovery, textiles, tissue engineering, wood, and various aspects of glycoscience. The journal emphasizes the central role of well-characterized carbohydrate polymers, highlighting their significance as the primary focus rather than a peripheral topic. Each paper must prominently feature at least one named carbohydrate polymer, evident in both citation and title, with a commitment to innovative research that advances scientific knowledge.