The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in PfACG1 and PfEHD. These proteins are implicated in intracellular trafficking, lipid utilization, and endocytosis, suggesting interference with these pathways as a potential mode of action. This preclinical candidate may offer the potential for a single low-dose cure for malaria.

恶性疟原虫对一线抗疟药的耐药性的出现和传播使得确定和开发具有不同作用模式的有效临床前候选药物势在必行。在这里，我们报告了 MMV688533 的鉴定结果，这是一种酰基胍，是在使用已知可击中人体细胞中高价值靶标的化合物进行全细胞筛选后开发的。MMV688533 在体外表现出快速的寄生虫清除能力，并且与已知的抗疟药没有交叉耐药性。在恶性疟原虫中NSG 小鼠模型 MMV688533 显示出持久的药代动力学特征和出色的安全性。选择研究显示耐药性低，PfACG1 和 PfEHD 点突变介导的效力适度丧失。这些蛋白质与细胞内运输、脂质利用和内吞作用有关，表明干扰这些途径是一种潜在的作用方式。这种临床前候选药物可能提供单一低剂量治疗疟疾的潜力。