Reaction hijacking of tyrosine tRNA synthetase as a new whole-of-life-cycle antimalarial strategy.

Abstract

Aminoacyl transfer RNA (tRNA) synthetases (aaRSs) are attractive drug targets, and we present class I and II aaRSs as previously unrecognized targets for adenosine 5'-monophosphate-mimicking nucleoside sulfamates. The target enzyme catalyzes the formation of an inhibitory amino acid-sulfamate conjugate through a reaction-hijacking mechanism. We identified adenosine 5'-sulfamate as a broad-specificity compound that hijacks a range of aaRSs and ML901 as a specific reagent a specific reagent that hijacks a single aaRS in the malaria parasite Plasmodium falciparum, namely tyrosine RS (PfYRS). ML901 exerts whole-life-cycle-killing activity with low nanomolar potency and single-dose efficacy in a mouse model of malaria. X-ray crystallographic studies of plasmodium and human YRSs reveal differential flexibility of a loop over the catalytic site that underpins differential susceptibility to reaction hijacking by ML901.

• Authors: Stanley C Xie, Riley D Metcalfe, Elyse Dunn, Craig J Morton, Shih-Chung Huang, Tanya Puhalovich, Yawei Du, Sergio Wittlin, Shuai Nie, Madeline R Luth, Liting Ma, Mi-Sook Kim, Charisse Flerida A Pasaje, Krittikorn Kumpornsin, Carlo Giannangelo, Fiona J Houghton, Alisje Churchyard, Mufuliat T Famodimu, Daniel C Barry, David L Gillett, Sumanta Dey, Clara C Kosasih, William Newman, Jacquin C Niles, Marcus C S Lee, Jake Baum, Sabine Ottilie, Elizabeth A Winzeler, Darren J Creek, Nicholas Williamson, Michael W Parker, Stephen Brand, Steven P Langston, Lawrence R Dick, Michael D W Griffin, Alexandra E Gould, Leann Tilley
• Journal: Science (New York, N.Y.) (Science) Vol. 376 Issue 6597 Pg. 1074-1079 (06 03 2022) ISSN: 1095-9203 [Electronic] United States
• PMID: 35653481 (Publication Type: Journal Article)

Chemical References

• Antimalarials
• Protozoan Proteins
• Sulfonic Acids
• sulfamic acid
• Tyrosine-tRNA Ligase
• Adenosine

Topics

• Adenosine (analogs & derivatives)
• Animals
• Antimalarials (chemistry, pharmacology, therapeutic use)
• Crystallography, X-Ray
• Humans
• Malaria, Falciparum (drug therapy, parasitology)
• Mice
• Molecular Targeted Therapy
• Plasmodium falciparum (drug effects, enzymology)
• Protein Biosynthesis (drug effects)
• Protein Conformation
• Protozoan Proteins (chemistry, metabolism)
• Sulfonic Acids (chemistry)
• Tyrosine-tRNA Ligase (chemistry, metabolism)