6L3X

Discovery of novel peptidomimetic boronate ClpP inhibitors with noncanonical enzyme mechanism as potent virulence blockers in vitro and in vivo

6L3X の概要

• エントリーDOI: 10.2210/pdb6l3x/pdb
• 分子名称: ATP-dependent Clp protease proteolytic subunit, [(1~{R})-1-[[(2~{S})-2-[[2,5-bis(chloranyl)phenyl]carbonylamino]-3-(1~{H}-indol-3-yl)propanoyl]amino]-3-methyl-butyl]boronic acid (3 entities in total)
• 機能のキーワード: s. aureus, caseinolytic protease p, hydrolase-inhibitor complex, hydrolase/inhibitor
• 由来する生物種: Staphylococcus aureus RF122
• タンパク質・核酸の鎖数: 14
• 化学式量合計: 279501.03

構造登録者

Luo, Y.F.,Bao, R.,Ju, Y.,He, L.H. (登録日: 2019-10-15, 公開日: 2020-08-26, 最終更新日: 2023-11-22)

主引用文献

Ju, Y.,He, L.,Zhou, Y.,Yang, T.,Sun, K.,Song, R.,Yang, Y.,Li, C.,Sang, Z.,Bao, R.,Luo, Y.
Discovery of Novel Peptidomimetic Boronate ClpP Inhibitors with Noncanonical Enzyme Mechanism as Potent Virulence Blockersin Vitroandin Vivo.
J.Med.Chem., 63:3104-3119, 2020

PubMed Abstract: Caseinolytic protease P (ClpP) is considered as a promising target for the treatment of infections. In an unbiased screen of 2632 molecules, a peptidomimetic boronate, MLN9708, was found to be a potent suppressor of ClpP function. A time-saving and cost-efficient strategy integrating 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 was the most active inhibitor and showed reversible covalent binding to ClpP while did not destabilize the tetradecameric structure of ClpP. The crystal structure of -ClpP complex provided mechanistic insight into the covalent binding mode of peptidomimetic boronate and ClpP. Furthermore, could bind endogenous ClpP in cells and exhibited significant efficacy in attenuating virulence and .

PubMed: 32031798
DOI: 10.1021/acs.jmedchem.9b01746

実験手法

X-RAY DIFFRACTION (2.3054 Å)