期刊
SCIENCE TRANSLATIONAL MEDICINE
卷 9, 期 387, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aad9735
关键词
-
资金
- Medicines for Malaria Venture (MMV) [MMV09/0002]
- University of Cape Town
- South African Medical Research Council
- South African Research Chairs Initiative of the Department of Science and Technology through the South African National Research Foundation
- NIH [R01 AI109023, R01 AI103058]
- MMV
- Wellcome Trust [WT078285]
- MRC [MR/N00227X/1] Funding Source: UKRI
- Medical Research Council [MR/N00227X/1] Funding Source: researchfish
As part of the global effort toward malaria eradication, phenotypic whole-cell screening revealed the 2-aminopyridine class of small molecules as a good starting point to develop new antimalarial drugs. Stemming from this series, we found that the derivative, MMV390048, lacked cross-resistance with current drugs used to treat malaria. This compound was efficacious against all Plasmodium life cycle stages, apart from late hypnozoites in the liver. Efficacy was shown in the humanized Plasmodium falciparum mouse model, and modest reductions in mouse-to-mouse transmission were achieved in the Plasmodium berghei mouse model. Experiments in monkeys revealed the ability of MMV390048 to be used for full chemoprotection. Although MMV390048 was not able to eliminate liver hypnozoites, it delayed relapse in a Plasmodium cynomolgi monkey model. Both genomic and chemoproteomic studies identified a kinase of the Plasmodium parasite, phosphatidylinositol 4-kinase, as the molecular target of MMV390048. The ability of MMV390048 to block all life cycle stages of the malaria parasite suggests that this compound should be further developed and may contribute to malaria control and eradication as part of a single-dose combination treatment.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据