| Autor: |
Xie, Stanley C., Tai, Chia-Wei, Morton, Craig J., Ma, Liting, Huang, Shih-Chung, Wittlin, Sergio, Du, Yawei, Hu, Yongbo, Dogovski, Con, Salimimarand, Mina, Griffin, Robert, England, Dylan, de la Cruz, Elisa, Deni, Ioanna, Yeo, Tomas, Burkhard, Anna Y., Striepen, Josefine, Schindler, Kyra A., Crespo, Benigno, Gamo, Francisco J. |
| Zdroj: |
PLoS Pathogens; 12/9/2024, Vol. 20 Issue 12, p1-28, 28p |
| Abstrakt: |
The Plasmodium falciparum cytoplasmic tyrosine tRNA synthetase (PfTyrRS) 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 PfTyrRS. 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 PfTyrRS enzyme. A crystal structure of the PfTyrRS/ Tyr-ML471 complex offers insights into improved potency, while molecular docking into UAE provides a rationale for improved selectivity. Author summary: Malaria is a devastating disease caused by the Plasmodium parasite, with more than 200 million cases and 600,000 deaths reported in 2022. Worryingly, the emergence of clinically artemisinin-resistant P. falciparum was first identified in Southeast Asia and more recently detected in Africa. This imposes a significant burden on the healthcare systems of the world's poorest countries. This study continues our previous effort to develop a series of nucleoside sulfamates that targets the P. falciparum cytoplasmic tyrosine tRNA synthetase (PfTyrRS), via a reaction hijacking mechanism. We explored the potency and selectivity of nucleoside sulfamate derivatives and identified a front runner compound, ML471, that shows potent activity against malaria parasites but low toxicity to human cells. Moreover, ML471 shows activity against multiple life stages of the parasite and exhibits single-dose oral efficacy in the SCID mouse model of P. falciparum malaria. We confirmed ML471 is a potent reaction hijacking inhibitor that is converted to Tyr-ML471 by the recombinant PfTyrRS enzyme. The crystal structure of Tyr-ML471 bound PfTyrRS offers molecular insights that could guide future drug design. Taken together, our findings provide a promising direction for developing new antimalarials. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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