Repositioning and Characterization of 1-(Pyridin-4-yl)pyrrolidin-2-one Derivatives as Plasmodium Cytoplasmic Prolyl-tRNA Synthetase Inhibitors

Masanori Okaniwa, Akira Shibata, Atsuko Ochida, Yuichiro Akao, Karen L. White, David M. Shackleford, Sandra Duffy, Leonardo Lucantoni, Sumanta Dey, Josefine Striepen, Tomas Yeo, Sachel Mok, Anna Caroline C. Aguiar, Angelika Sturm, Benigno Crespo, Laura M. Sanz, Alisje Churchyard, Jake Baum, Dhelio B. Pereira, Rafael V.C. GuidoKoen J. Dechering, Sergio Wittlin, Anne Catrin Uhlemann, David A. Fidock, Jacquin C. Niles, Vicky M. Avery, Susan A. Charman, Benoît Laleu

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13 Citations (Scopus)

Abstract

Prolyl-tRNA synthetase (PRS) is a clinically validated antimalarial target. Screening of a set of PRS ATP-site binders, initially designed for human indications, led to identification of 1-(pyridin-4-yl)pyrrolidin-2-one derivatives representing a novel antimalarial scaffold. Evidence designates cytoplasmic PRS as the drug target. The frontrunner 1 and its active enantiomer 1-S exhibited low-double-digit nanomolar activity against resistant Plasmodium falciparum (Pf) laboratory strains and development of liver schizonts. No cross-resistance with strains resistant to other known antimalarials was noted. In addition, a similar level of growth inhibition was observed against clinical field isolates of Pf and P. vivax. The slow killing profile and the relative high propensity to develop resistance in vitro (minimum inoculum resistance of 8 × 105 parasites at a selection pressure of 3 × IC50) constitute unfavorable features for treatment of malaria. However, potent blood stage and antischizontal activity are compelling for causal prophylaxis which does not require fast onset of action. Achieving sufficient on-target selectivity appears to be particularly challenging and should be the primary focus during the next steps of optimization of this chemical series. Encouraging preliminary off-target profile and oral efficacy in a humanized murine model of Pf malaria allowed us to conclude that 1-(pyridin-4-yl)pyrrolidin-2-one derivatives represent a promising starting point for the identification of novel antimalarial prophylactic agents that selectively target Plasmodium PRS.

Original languageEnglish
Pages (from-to)1680–1689
Number of pages10
JournalACS Infectious Diseases
Volume7
Issue number6
DOIs
Publication statusPublished - 30 Apr 2021

Keywords

  • malaria
  • Plasmodium
  • prolyl-tRNA synthetase
  • PRS

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