Journal Article

A potent and selective reaction hijacking inhibitor of Plasmodium falciparum tyrosine tRNA synthetase exhibits single dose oral efficacy in vivo

Tilley, Leann, Brand, Stephen L., Hu, Yongbo, Dogovski, Con, Griffin, Robert, Gamo, Francisco J., van der Laak, Rianne, Striepen, Josefine, Hutton, Craig A., Fidock, David A., Langston, Steven, Creek, Darren J., Rabie, Tayla, Koolen, Karin M. J., Khandokar, Yogesh, Delves, Michael J., Deni, Ioanna, Burkhard, Anna Y., England, Dylan, Morton, Craig J., Salimimarand, Mina, Ma, Liting, Birkholtz, Lyn-Marié, Griffin, Michael D. W., Tai, Chia-Wei, Guido, Rafael V. C., Gould, Alexandra E., Yeo, Tomas, Aguiar, Anna C. C., Crespo, Benigno, Schindler, Kyra A., Wittlin, Sergio, de la Cruz, Elisa, Huang, Shih-Chung, Famodimu, Mufuliat T., Bolsher, Judith, Dick, Lawrence R., Du, Yawei, Pereira, Dhelio B., Xie, Stanley C.

2024

Overview

The Plasmodium falciparum cytoplasmic tyrosine tRNA synthetase ( Pf TyrRS) is an attractive drug target that is susceptible to reaction-hijacking by AMP-mimicking nucleoside sulfamates. We previously identified an exemplar pyrazolopyrimidine ribose sulfamate, ML901, as a potent reaction hijacking inhibitor of Pf TyrRS. Here we examined the stage specificity of action of ML901, showing very good activity against the schizont stage, but lower trophozoite stage activity. We explored a series of ML901 analogues and identified ML471, which exhibits improved potency against trophozoites and enhanced selectivity against a human cell line. Additionally, it has no inhibitory activity against human ubiquitin-activating enzyme (UAE) in vitro . ML471 exhibits low nanomolar activity against asexual blood stage P . falciparum and potent activity against liver stage parasites, gametocytes and transmissible gametes. It is fast-acting and exhibits a long in vivo half-life. ML471 is well-tolerated and shows single dose oral efficacy in the SCID mouse model of P . falciparum malaria. We confirm that ML471 is a reaction hijacking inhibitor that is converted into a tight binding Tyr-ML471 conjugate by the Pf TyrRS enzyme. A crystal structure of the Pf TyrRS/ Tyr-ML471 complex offers insights into improved potency, while molecular docking into UAE provides a rationale for improved selectivity.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adenosine / Administration, Oral / Animals / Antimalarials - pharmacology / Antiparasitic agents / Biology and Life Sciences / Control / Councils / Crystal structure / Dosage and administration / Drug dosages / Effectiveness / Enzyme inhibitors / Enzyme Inhibitors - pharmacology / Enzymes / Gametes / Gametocytes / Humans / Inhibitors / Libraries / Ligases / Malaria / Malaria, Falciparum - drug therapy / Malaria, Falciparum - parasitology / Medical research / Medicine and Health Sciences / Mice / Mice, SCID / Molecular docking / Parasites / Pharmaceuticals / Pharmacology, Experimental / Physical Sciences / Physiological aspects / Plasmodium falciparum / Plasmodium falciparum - drug effects / Plasmodium falciparum - enzymology / Protozoan Proteins - antagonists & inhibitors / Protozoan Proteins - metabolism / Pyrimidines - pharmacology / Ribose / Selectivity / Therapeutic targets / Toxicity / Transfer RNA / tRNA Tyr / Trophozoites / Tyrosine / Tyrosine-tRNA Ligase - antagonists & inhibitors / Tyrosine-tRNA Ligase - metabolism / Ubiquitin / Vector-borne diseases