Reaction hijacking of tyrosine tRNA synthetase as a new whole-of-life-cycle antimalarial strategy.
Science
; 376(6597): 1074-1079, 2022 06 03.
Article
en En
| MEDLINE
| ID: mdl-35653481
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.
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Banco de datos:
MEDLINE
Asunto principal:
Plasmodium falciparum
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Biosíntesis de Proteínas
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Tirosina-ARNt Ligasa
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Proteínas Protozoarias
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Malaria Falciparum
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Terapia Molecular Dirigida
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Antimaláricos
Límite:
Animals
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Humans
Idioma:
En
Año:
2022
Tipo del documento:
Article