التفاصيل البيبلوغرافية
العنوان: |
Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase |
المؤلفون: |
Stanley C. Xie, Yinuo Wang, Craig J. Morton, Riley D. Metcalfe, Con Dogovski, Charisse Flerida A. Pasaje, Elyse Dunn, Madeline R. Luth, Krittikorn Kumpornsin, Eva S. Istvan, Joon Sung Park |
المصدر: |
Nature, Nature Communications. 15(1):1-18 |
سنة النشر: |
2024 |
الوصف: |
Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold. We show that the exemplar, OSM-S-106, has potent activity against parasite cultures, low mammalian cell toxicity and low propensity for resistance development. In vitro evolution of resistance using a slow ramp-up approach pointed to the Plasmodium falciparum cytoplasmic asparaginyl-tRNA synthetase (PfAsnRS) as the target, consistent with our finding that OSM-S-106 inhibits protein translation and activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that inhibition of PfAsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less susceptible to this reaction hijacking mechanism. X-ray crystallographic studies of human AsnRS in complex with inhibitor adducts and docking of pro-inhibitors into a model of Asn-tRNA-bound PfAsnRS provide insights into the structure-activity relationship and the selectivity mechanism. |
نوع الوثيقة: |
redif-article |
اللغة: |
English |
DOI: |
10.1038/s41467-024-45224 |
الإتاحة: |
https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-45224-z.html |
رقم الأكسشن: |
edsrep.a.nat.natcom.v15y2024i1d10.1038.s41467.024.45224.z |
قاعدة البيانات: |
RePEc |