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

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    Author(s)
    Okaniwa, Masanori
    Shibata, Akira
    Ochida, Atsuko
    Akao, Yuichiro
    White, Karen L
    Shackleford, David M
    Duffy, Sandra
    Lucantoni, Leonardo
    Dey, Sumanta
    Striepen, Josefine
    Yeo, Tomas
    Mok, Sachel
    Aguiar, Anna Caroline C
    Avery, Vicky M
    et al.
    Griffith University Author(s)
    Avery, Vicky M.
    Lucantoni, Leonardo
    Duffy, Sandra
    Year published
    2021
    Metadata
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    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 ...
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    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.
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    Journal Title
    ACS Infectious Diseases
    DOI
    https://doi.org/10.1021/acsinfecdis.1c00020
    Copyright Statement
    © 2021 The Authors. Published by American Chemical Society. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International (CC BY-NC-ND 4.0) License, which permits unrestricted, non-commercial use, distribution and reproduction in any medium, providing that the work is properly cited.
    Note
    This publication has been entered in Griffith Research Online as an advanced online version.
    Subject
    Medical microbiology
    PRS
    Plasmodium
    malaria
    prolyl-tRNA synthetase
    Publication URI
    http://hdl.handle.net/10072/404268
    Collection
    • Journal articles

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