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, Khandokar Yogesh, Hutton Craig A, Rabie Tayla, Birkholtz Lyn-Marié, Famodimu Mufuliat T, Delves Michael J, Bolsher Judith, Koolen Karin M J, van der Laak Rianne, Aguiar Anna C C, Pereira Dhelio B, Guido Rafael V C, Creek Darren J, Fidock David A, Dick Lawrence R, Brand Stephen L, Gould Alexandra E, Langston Steven, Griffin Michael D W, Tilley Leann
Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, Victoria, Australia.
Drug Delivery Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
PLoS Pathog. 2024 Dec 9;20(12):e1012429. doi: 10.1371/journal.ppat.1012429. eCollection 2024 Dec.
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.
恶性疟原虫胞质酪氨酸tRNA合成酶（PfTyrRS）是一个有吸引力的药物靶点，易被AMP模拟核苷氨基磺酸盐劫持反应。我们之前鉴定出一种吡唑并嘧啶核糖氨基磺酸盐ML901，作为PfTyrRS的一种有效的反应劫持抑制剂。在此，我们研究了ML901的作用阶段特异性，结果显示其对裂殖体阶段活性非常好，但对滋养体阶段活性较低。我们探索了一系列ML901类似物，鉴定出ML471，它对滋养体的效力有所提高，对人细胞系的选择性增强。此外，它在体外对人泛素激活酶（UAE）没有抑制活性。ML471对恶性疟原虫无性血液阶段表现出低纳摩尔活性，对肝期寄生虫、配子体和可传播配子具有强效活性。它起效快，体内半衰期长。ML471耐受性良好，在恶性疟原虫疟疾的SCID小鼠模型中显示出单剂量口服疗效。我们证实ML471是一种反应劫持抑制剂，可被PfTyrRS酶转化为紧密结合的Tyr-ML471缀合物。PfTyrRS/Tyr-ML471复合物的晶体结构为效力提高提供了见解，而对UAE的分子对接为选择性提高提供了理论依据。
