Elucidating the path to Plasmodium prolyl-tRNA synthetase inhibitors that overcome halofuginone resistance.

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

Nature communications, Volume: 13, Issue: 1
August 25, 2022
Mark A Tye MA, N Connor Payne NC, Catrine Johansson C, Kritika Singh K, Sofia A Santos SA, Lọla Fagbami L, Akansha Pant A, Kayla Sylvester K, Madeline R Luth MR, Sofia Marques S, Malcolm Whitman M, Maria M Mota MM, Elizabeth A Winzeler EA, Amanda K Lukens AK, Emily R Derbyshire ER, Udo Oppermann U, Dyann F Wirth DF, Ralph Mazitschek R

The development of next-generation antimalarials that are efficacious against the human liver and asexual blood stages is recognized as one of the world’s most pressing public health challenges. In recent years, aminoacyl-tRNA synthetases, including prolyl-tRNA synthetase, have emerged as attractive targets for malaria chemotherapy. We describe the development of a single-step biochemical assay for Plasmodium and human prolyl-tRNA synthetases that overcomes critical limitations of existing technologies and enables quantitative inhibitor profiling with high sensitivity and flexibility. Supported by this assay platform and co-crystal structures of representative inhibitor-target complexes, we develop a set of high-affinity prolyl-tRNA synthetase inhibitors, including previously elusive aminoacyl-tRNA synthetase triple-site ligands that simultaneously engage all three substrate-binding pockets. Several compounds exhibit potent dual-stage activity against Plasmodium parasites and display good cellular host selectivity. Our data inform the inhibitor requirements to overcome existing resistance mechanisms and establish a path for rational development of prolyl-tRNA synthetase-targeted anti-malarial therapies.

Courtesy of the U.S. National Library of Medicine