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研究表明酪氨酸tRNA合成酶可作为疟疾治疗的靶点
作者:小柯机器人 发布时间:2022/6/4 23:44:31

澳大利亚墨尔本大学Leann Tilley团队的最新研究表明,劫持酪氨酸氨酰转移RNA(tRNA)合成酶(aaRS)反应是一种新的全生命周期的抗疟方法。相关论文于2022年6月3日发表在《科学》杂志上。

tRNA合成酶是非常有潜力的药物靶点,研究人员将I类和II类aaRS作为新的5'-单磷酸腺苷模拟核苷氨基磺酸盐的靶点。靶酶通过反应劫持机制催化形成抑制性氨基酸-氨基磺酸盐偶联物。研究人员发现腺苷5'-氨基磺酸盐是一种广泛特异性的化合物,它可以劫持一系列 aaRS,而ML901则是一种特异性试剂,一种可以劫持恶性疟原虫中单个aaRS的特异性试剂,即酪氨酸RS (PfYRS)。

ML901在疟疾小鼠模型中发挥全生命周期的杀灭活性,具有低纳摩尔效力和单剂量效力。疟原虫和人类YRS的X射线晶体学研究揭示了催化位点上环的不同柔韧性,这支持了对ML901劫持反应的不同敏感性。

附:英文原文

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

Author: 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

Issue&Volume: 2022-06-03

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.

DOI: abn0611

Source: https://www.science.org/doi/10.1126/science.abn0611

 

期刊信息
Science:《科学》,创刊于1880年。隶属于美国科学促进会,最新IF:41.037