Discovery of Novel Peptidomimetic Boronate ClpP Inhibitors with Noncanonical Enzyme Mechanism as Potent Virulence Blockers in Vitro and in Vivo.,Journal of Medicinal Chemistry

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Discovery of Novel Peptidomimetic Boronate ClpP Inhibitors with Noncanonical Enzyme Mechanism as Potent Virulence Blockers in Vitro and in Vivo.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-02-07 , DOI: 10.1021/acs.jmedchem.9b01746
Yuan Ju ₁ , Lihui He ₁ , Yuanzheng Zhou ₁ , Tao Yang _{1,

2} , Ke Sun ₁ , Rao Song ₁ , Yang Yang ₁ , Chengwei Li _{1,

3} , Zitai Sang ₄ , Rui Bao ₁ , Youfu Luo ₁

Affiliation

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.

中文翻译：

发现具有非典型酶机制的新型拟肽硼酸盐ClpP抑制剂，作为体内和体外的强毒力阻断剂。

酪蛋白水解蛋白酶P（ClpP）被认为是治疗金黄色葡萄球菌感染的有希望的靶标。在2632个分子的无偏筛选中，拟肽的硼酸酯MLN9708被发现是SaClpP功能的有效抑制剂。部署了一种节省时间和成本效益的策略，该策略集成了计算机位置扫描，多步微型化合成和生物活性测试，以优化该命中化合物，并导致对结构-活性关系的快速探索。来自小型化合成的150种化合物中有5种显示出更高的抑制活性。化合物43Hf是活性最高的抑制剂，并显示与SaClpP可逆的共价结合，而不会破坏SaClpP的十四聚体结构的稳定性。43Hf-SaClpP复合物的晶体结构提供了对拟肽硼酸酯和SaClpP的共价结合模式的机械洞察力。此外，43Hf可以结合金黄色葡萄球菌细胞中的内源性ClpP，并在体内和体外显示出减弱金黄色葡萄球菌毒力的显着功效。

更新日期：2020-02-20

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