Repositioning and Characterization of 1-(Pyridin-4-yl)pyrrolidin-2-one Derivatives as Plasmodium Cytoplasmic Prolyl-tRNA Synthetase Inhibitors
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acsinfecdis.1c00020.pdf
Description
Published version
Size
1.59 MB
Format
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Checksum (MD5)
147756269c9db5d63201a807fe1747a3
Author(s)
Okaniwa, Masanori
Shibata, Akira
Ochida, Atsuko
Akao, Yuichiro
White, Karen L
Shackleford, David M
Duffy, Sandra
Lucantoni, Leonardo
Dey, Sumanta
Striepen, Josefine
Date Issued
2021
Journal
ACS Infectious Diseases
Publisher
American Chemical Society (ACS)
Version
Final published version
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.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
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DOI of Published Version
10.1021/ACSINFECDIS.1C00020
