Xie Stanley C, Wang Yinuo, Morton Craig J, Metcalfe Riley D, Dogovski Con, Pasaje Charisse Flerida A, Dunn Elyse, Luth Madeline R, Kumpornsin Krittikorn, Istvan Eva S, Park Joon Sung, Fairhurst Kate J, Ketprasit Nutpakal, Yeo Tomas, Yildirim Okan, Bhebhe Mathamsanqa N, Klug Dana M, Rutledge Peter J, Godoy Luiz C, Dey Sumanta, De Souza Mariana Laureano, Siqueira-Neto Jair L, Du Yawei, Puhalovich Tanya, Amini Mona, Shami Gerry, Loesbanluechai Duangkamon, Nie Shuai, Williamson Nicholas, Jana Gouranga P, Maity Bikash C, Thomson Patrick, Foley Thomas, Tan Derek S, Niles Jacquin C, Han Byung Woo, Goldberg Daniel E, Burrows Jeremy, Fidock David A, Lee Marcus C S, Winzeler Elizabeth A, Griffin Michael D W, Todd Matthew H, Tilley Leann
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, United Kingdom.
Res Sq. 2023 Jul 27:rs.3.rs-3198291. doi: 10.21203/rs.3.rs-3198291/v1.
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. evolution of resistance using a slow ramp-up approach pointed to the cytoplasmic asparaginyl tRNA synthetase (AsnRS) 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 AsnRS 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 AsnRS provide insights into the structure activity relationship and the selectivity mechanism.
疟疾对人类健康构成巨大威胁。由于对目前使用的药物的耐药性不断增加，迫切需要具有新型作用机制的突破性化合物。在此，我们探索基于嘧啶的磺胺类化合物，作为一类具有类药物物理参数且合成途径可及的新型低分子量抑制剂。我们表明，范例化合物OSM-S-106对寄生虫培养物具有强效活性，对哺乳动物细胞毒性低，且产生耐药性的倾向低。使用缓慢递增方法进行的耐药性进化研究表明，细胞质天冬酰胺基tRNA合成酶（AsnRS）是靶点，这与我们发现OSM-S-106抑制蛋白质翻译并激活氨基酸饥饿反应一致。靶向质谱分析证实OSM-S-106是一种前体抑制剂，并且对AsnRS的抑制是通过酶介导产生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。对与抑制剂加合物复合的人AsnRS进行的X射线晶体学研究以及将前体抑制剂对接至Asn-tRNA结合的AsnRS模型中，为结构活性关系和选择性机制提供了见解。
