Discovery of Novel Peptidomimetic Boronate ClpP Inhibitors with Noncanonical Enzyme Mechanism as Potent Virulence Blockers in Vitro and in Vivo
Discovery of Novel Peptidomimetic Boronate ClpP Inhibitors with Noncanonical Enzyme Mechanism as Potent Virulence Blockers in Vitro and in Vivo
复制标题
发现具有非经典酶机制的新型肽模拟硼酸酯 ClpP 抑制剂作为体外和体内有效的毒力阻断剂。
DOI：
10.1021/acs.jmedchem.9b01746
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发表时间：
2020-03-26
影响因子：
7.3
通讯作者：
Luo, Youfu
中科院分区：
文献类型：
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作者：
Ju, Yuan;He, Lihui;Luo, Youfu
酪蛋白水解酶P(ClpP)被认为是治疗金黄色葡萄球菌感染的一个有前途的靶点。在2632个分子的无偏筛选中，一种模拟多肽的硼酸盐MLN9708被发现是SaClpP功能的有效抑制者。采用了一种集电子位置扫描、多步骤小型化合成和生物活性测试于一体的节省时间和成本高效的策略来优化这种HIT化合物，并导致快速探索构效关系。从小型化合成的150个化合物中，有5个化合物显示出更好的抑制活性。化合物43Hf是活性最高的抑制剂，与SaClpP呈现可逆的共价结合，但不破坏SaClpP的十四聚体结构。~(43)Hf-SaClpP络合物的晶体结构提供了模拟多肽的硼酸盐与SaClpP的共价结合模式的机制。此外，43Hf能与金黄色葡萄球菌细胞内源性ClpP结合，对金黄色葡萄球菌的体内外毒力有明显的抑制作用。
Caseinolytic protease P (ClpP) is considered as a promising target for the treatment of Staphylococcus aureus infections. In an unbiased screen of 2632 molecules, a peptidomimetic boronate, MLN9708, was found to be a potent suppressor of SaClpP function. A time-saving and cost-efficient strategy integrating in silico position scanning, multistep miniaturized synthesis, and bioactivity testing was deployed for optimization of this hit compound and led to fast exploration of structure-activity relationships. Five of 150 compounds from the miniaturized synthesis exhibited improved inhibitory activity. Compound 43Hf was the most active inhibitor and showed reversible covalent binding to SaClpP while did not destabilize the tetradecameric structure of SaClpP. The crystal structure of 43Hf-SaClpP complex provided mechanistic insight into the covalent binding mode of peptidomimetic boronate and SaClpP. Furthermore, 43Hf could bind endogenous ClpP in S. aureus cells and exhibited significant efficacy in attenuating S. aureus virulence in vitro and in vivo.