Research ArticleMalaria

Antimalarial efficacy of MMV390048, an inhibitor of Plasmodium phosphatidylinositol 4-kinase

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Science Translational Medicine  26 Apr 2017:
Vol. 9, Issue 387, eaad9735
DOI: 10.1126/scitranslmed.aad9735

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A new antimalarial in the armamentarium

Paquet et al. screened a small-molecule library against the human malaria parasite, Plasmodium falciparum, and identified the 2-aminopyridine chemical class with potent activity. The optimized compound from this class, MMV390048, was active against multiple parasite life cycle stages, in both the mammalian host and the mosquito vector, and also killed drug-resistant parasites. MMV390048 killed the malaria parasite by blocking the parasite’s phosphatidylinositol 4-kinase (PI4K) and was able to protect monkeys from malaria infection. MMV390048 has potential as a new antimalarial drug that may contribute to global malaria eradication efforts.

Abstract

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.

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