Okaniwa Masanori, Shibata Akira, Ochida Atsuko, Akao Yuichiro, White Karen L, Shackleford David M, Duffy Sandra, Lucantoni Leonardo, Dey Sumanta, Striepen Josefine, Yeo Tomas, Mok Sachel, Aguiar Anna Caroline C, Sturm Angelika, Crespo Benigno, Sanz Laura M, Churchyard Alisje, Baum Jake, Pereira Dhelio B, Guido Rafael V C, Dechering Koen J, Wittlin Sergio, Uhlemann Anne-Catrin, Fidock David A, Niles Jacquin C, Avery Vicky M, Charman Susan A, Laleu Benoît
Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
ACS Infect Dis. 2021 Jun 11;7(6):1680-1689. doi: 10.1021/acsinfecdis.1c00020. Epub 2021 Apr 30.
Prolyl-tRNA synthetase (PRS) is a clinically validated antimalarial target. Screening of a set of PRS ATP-site binders, initially designed for human indications, led to identification of 1-(pyridin-4-yl)pyrrolidin-2-one derivatives representing a novel antimalarial scaffold. Evidence designates cytoplasmic PRS as the drug target. The frontrunner and its active enantiomer exhibited low-double-digit nanomolar activity against resistant () laboratory strains and development of liver schizonts. No cross-resistance with strains resistant to other known antimalarials was noted. In addition, a similar level of growth inhibition was observed against clinical field isolates of and . The slow killing profile and the relative high propensity to develop resistance (minimum inoculum resistance of 8 × 10 parasites at a selection pressure of 3 × IC) constitute unfavorable features for treatment of malaria. However, potent blood stage and antischizontal activity are compelling for causal prophylaxis which does not require fast onset of action. Achieving sufficient on-target selectivity appears to be particularly challenging and should be the primary focus during the next steps of optimization of this chemical series. Encouraging preliminary off-target profile and oral efficacy in a humanized murine model of malaria allowed us to conclude that 1-(pyridin-4-yl)pyrrolidin-2-one derivatives represent a promising starting point for the identification of novel antimalarial prophylactic agents that selectively target PRS.
脯氨酰 - tRNA合成酶（PRS）是一个经过临床验证的抗疟靶点。对一组最初针对人类适应症设计的PRS ATP位点结合剂进行筛选，从而鉴定出代表新型抗疟骨架的1 - （吡啶 - 4 - 基）吡咯烷 - 2 - 酮衍生物。有证据表明细胞质PRS是药物靶点。领先化合物及其活性对映体对耐药的（）实验室菌株和肝期裂殖体表现出低两位数纳摩尔活性。未发现与对其他已知抗疟药耐药的菌株有交叉耐药性。此外，对和的临床现场分离株观察到了相似水平的生长抑制。缓慢的杀伤特性以及产生耐药性的相对高倾向（在3×IC的选择压力下最小接种量耐药性为8×10个寄生虫）构成了疟疾治疗的不利特征。然而，强效的血期和抗裂殖体活性对于不需要快速起效的病因性预防来说是很有吸引力的。实现足够的靶点选择性似乎特别具有挑战性，应该是该化学系列优化后续步骤的主要重点。在疟疾人源化小鼠模型中令人鼓舞的初步脱靶特征和口服疗效使我们得出结论，1 - （吡啶 - 4 - 基）吡咯烷 - 2 - 酮衍生物是鉴定选择性靶向PRS的新型抗疟预防药物的一个有前景的起点。
