Inhibition of Plasmodium falciparum Lysyl-tRNA Synthetase via a Piperidine-Ring Scaffold Inspired Cladosporin Analogues

Palak Babbar, Mizuki Sato, Yogavel Manickam, Siddhartha Mishra, Karl Harlos, Swati Gupta, Suhel Parvez, Haruhisa Kikuchi, Amit Sharma

研究成果: Article査読

抄録

Plasmodium falciparum lysyl-tRNA synthetase (PfKRS) represents a promising therapeutic anti-malarial target. Cladosporin was identified as a selective and potent PfKRS inhibitor but lacks metabolic stability. Here, we report chemical synthesis, biological evaluation and structural characterization of analogues where the tetrahydropyran (THP) frame of cladosporin is replaced with the piperidine ring bearing functional group variations. Thermal binding, enzymatic, kinetic and parasitic assays complemented with X-ray crystallography reveal compounds that are moderate in potency. Co-crystals of Cla−B and Cla−C with PfKRS reveal key atomic configurations that allow drug binding to and inhibition of the enzyme. Collectively these piperidine ring scaffold inhibitors lay a framework for further structural editing and functional modifications of the cladosporin scaffold to obtain a potent lead.

本文言語English
ページ(範囲)2468-2477
ページ数10
ジャーナルChemBioChem
22
14
DOI
出版ステータスPublished - 2021 7 15

ASJC Scopus subject areas

  • 生化学
  • 分子医療
  • 分子生物学
  • 有機化学

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