Publications [#365594] of Emily R. Derbyshire

Journal Articles

1. Tye, MA; Payne, NC; Johansson, C; Singh, K; Santos, SA; Fagbami, L; Pant, A; Sylvester, K; Luth, MR; Marques, S; Whitman, M; Mota, MM; Winzeler, EA; Lukens, AK; Derbyshire, ER; Oppermann, U; Wirth, DF; Mazitschek, R, Elucidating the path to Plasmodium prolyl-tRNA synthetase inhibitors that overcome halofuginone resistance., Nature communications, vol. 13 no. 1 (August, 2022), pp. 4976 [doi]
   (last updated on 2024/12/31)

   Abstract:
   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.