Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC, 3010, Australia.
School of Pharmacy, University College London, London, WC1N 1AX, UK.
Nat Commun. 2024 Jan 31;15(1):937. doi: 10.1038/s41467-024-45224-z.
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.
疟疾对人类健康构成了巨大威胁。由于目前使用的药物的抗药性不断增加，因此迫切需要具有新型作用机制的突破性化合物。在这里，我们探索嘧啶基磺酰胺作为一种具有类似药物的物理参数和可合成的支架的新型低分子量抑制剂类别。我们表明，典范化合物 OSM-S-106 对寄生虫培养物具有很强的活性，对哺乳动物细胞毒性低，且不易产生耐药性。使用缓慢上升的方法进行体外耐药性进化表明，恶性疟原虫细胞质天冬酰胺-tRNA 合成酶（PfAsnRS）是靶标，这与我们发现的 OSM-S-106 抑制蛋白质翻译并激活氨基酸饥饿反应一致。靶向质谱证实 OSM-S-106 是一种前抑制剂，并且 PfAsnRS 的抑制是通过酶介导的产生 Asn-OSM-S-106 加合物来实现的。人 AsnRS 对这种反应劫持机制的敏感性要低得多。与抑制剂加合物结合的人 AsnRS 的 X 射线晶体学研究以及前抑制剂在 PfAsnRS 结合 Asn-tRNA 模型中的对接提供了对结构-活性关系和选择性机制的深入了解。
