The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to Plasmodium falciparum parasite resistance.
The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to Plasmodium falciparum parasite resistance.
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DOI：
10.1126/scitranslmed.abg6013
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发表时间：
2021-07-21
影响因子：
17.1
通讯作者：
Leroy D
中科院分区：
文献类型：
--
作者：
Murithi JM;Pascal C;Bath J;Boulenc X;Gnädig NF;Pasaje CFA;Rubiano K;Yeo T;Mok S;Klieber S;Desert P;Jiménez-Díaz MB;Marfurt J;Rouillier M;Cherkaoui-Rbati MH;Gobeau N;Wittlin S;Uhlemann AC;Price RN;Wirjanata G;Noviyanti R;Tumwebaze P;Cooper RA;Rosenthal PJ;Sanz LM;Gamo FJ;Joseph J;Singh S;Bashyam S;Augereau JM;Giraud E;Bozec T;Vermat T;Tuffal G;Guillon JM;Menegotto J;Sallé L;Louit G;Cabanis MJ;Nicolas MF;Doubovetzky M;Merino R;Bessila N;Angulo-Barturen I;Baud D;Bebrevska L;Escudié F;Niles JC;Blasco B;Campbell S;Courtemanche G;Fraisse L;Pellet A;Fidock DA;Leroy D
恶性疟原虫对一线抗疟药物耐药性的出现和传播，迫切需要鉴定和开发具有不同作用模式的有效临床前候选药物。在这里，我们报告了MMV688533的鉴定，MMV688533是一种酰基胍，是在使用已知在人类细胞中击中高价值靶标的化合物进行全细胞筛选后开发的。MMV688533在体外显示出快速寄生虫清除，并且与已知抗疟药无交叉耐药性。在恶性疟原虫NSG小鼠模型中，MMV688533显示出持久的药代动力学特征和优异的安全性。选择研究显示耐药倾向较低，PfACG1和PfEHD点突变介导的效价适度丧失。这些蛋白质参与细胞内运输、脂质利用和内吞作用，表明干扰这些途径是一种潜在的作用模式。这种临床前候选药物可能为疟疾的单一低剂量治疗提供潜力。
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.
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影响因子：
14.9
作者：
Deitsch, KW;Driskill, CL;Wellems, TE
通讯作者：
Wellems, TE
影响因子：
3
作者：
Ding XC;Ubben D;Wells TN
通讯作者：
Wells TN
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6.7
作者：
Bane, Kartik S.;Lepper, Simone;Frischknecht, Friedrich
通讯作者：
Frischknecht, Friedrich
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作者：
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通讯作者：
Fidock, David A.
影响因子：
64.8
作者：
Gamo, Francisco-Javier;Sanz, Laura M.;Garcia-Bustos, Jose F.
通讯作者：
Garcia-Bustos, Jose F.