Reaction hijacking of tyrosine tRNA synthetase as a new whole-of-life-cycle antimalarial strategy
| Autor: | 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 |
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| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Science. 376:1074-1079 |
| ISSN: | 1095-9203 0036-8075 |
| Popis: | 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 ( Pf YRS). 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. |
| Databáze: | OpenAIRE |
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