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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)2468-2477
Number of pages10
JournalChemBioChem
Volume22
Issue number14
DOIs
Publication statusPublished - 2021 Jul 15

Keywords

  • anti-malaria agents
  • cladosporin
  • diastereomers
  • drug development
  • medicinal chemistry
  • stereoisomers
  • structure-activity relationships

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Organic Chemistry

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