Structure–Activity Relationship of Inositol Thiophosphate Analogs as Allosteric Activators of Clostridioides difficile Toxin B,Journal of Medicinal Chemistry

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Structure–Activity Relationship of Inositol Thiophosphate Analogs as Allosteric Activators of Clostridioides difficile Toxin B
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-09-10 , DOI: 10.1021/acs.jmedchem.4c01408
Rebecca Cummer ₁ , Félix Grosjean ₁ , Raphaël Bolteau ₁ , Seyed Ehsan Vasegh ₁ , Simon Veyron ₁ , Liam Keogh ₁ , Jean-François Trempe ₁ , Bastien Castagner ₁

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Clostridioides difficile is a bacterium that causes life-threatening intestinal infections. Infection symptoms are mediated by a toxin secreted by the bacterium. Toxin pathogenesis is modulated by the intracellular molecule, inositol-hexakisphosphate (IP6). IP6 binds to a cysteine protease domain (CPD) on the toxin, inducing autoproteolysis, which liberates a virulence factor in the cell cytosol. We developed second-generation IP6 analogs designed to induce autoproteolysis in the gut lumen, prior to toxin uptake, circumventing pathogenesis. We synthesized a panel of thiophosphate-/sulfate-containing IP6 analogs and characterized their toxin binding affinity, autoproteolysis induction, and cation interactions. Our top candidate was soluble in extracellular cation concentrations, unlike IP6. The IP6 analogs were more negatively charged than IP6, which improved affinity and stabilization of the CPD, enhancing toxin autoproteolysis. Our data illustrate the optimization of IP6 with thiophosphate biomimetic which are more capable of inducing toxin autoproteolysis than the native ligand, warranting further studies in vivo.

中文翻译：

肌醇硫代磷酸酯类似物作为艰难梭菌毒素 B 变构激活剂的构效关系

艰难梭菌是一种导致危及生命的肠道感染的细菌。感染症状是由细菌分泌的毒素介导的。毒素发病机制受细胞内分子肌醇-六磷酸（IP6）的调节。IP6 与毒素上的半胱氨酸蛋白酶结构域（CPD）结合，诱导自体蛋白水解，从而释放细胞胞质溶胶中的毒力因子。我们开发了第二代 IP6 类似物，旨在在毒素吸收之前在肠腔中诱导自体蛋白水解，从而规避发病机制。我们合成了一组含硫代磷酸盐/硫酸盐的 IP6 类似物，并表征了它们的毒素结合亲和力、自体蛋白水解诱导和阳离子相互作用。与 IP6 不同，我们的最佳候选药物可溶于细胞外阳离子浓度。IP6 类似物的负电荷比 IP6 更多，这提高了 CPD 的亲和力和稳定性，增强了毒素自体蛋白水解。我们的数据说明了硫磷酸盐仿生剂对 IP6 的优化，它比天然配体更能诱导毒素自体蛋白水解，值得在体内进行进一步研究。

更新日期：2024-09-10

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