6L40

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

Summary for 6L40

• Entry DOI: 10.2210/pdb6l40/pdb
• Descriptor: ATP-dependent Clp protease proteolytic subunit, [(1S)-3-methyl-1-[[(2S)-3-phenyl-2-(pyrazin-2-ylcarbonylamino)propanoyl]amino]butyl]boronic acid (3 entities in total)
• Functional Keywords: caseinolytic protease p (clpp), hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Staphylococcus aureus (strain bovine RF122 / ET3-1)
• Total number of polymer chains: 14
• Total formula weight: 274793.76

Authors

Luo, Y.F.,Bao, R.,Ju, Y.,He, L.H. (deposition date: 2019-10-15, release date: 2020-07-08, Last modification date: 2023-11-22)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.209 Å)