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

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 relapsein 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.

Antimalarial drug resistance: linking Plasmodium falciparum parasite biology to the clinic

“…117), an inhibitor of the lipid phosphatidylinositol 4-kinase (PI4K) that is required for correct membrane assembly around intracellular merozoites, just before their egress from a parasitized RBC (Fig. 1) 118 .…”

Plasmodium falciparum: Multidrug resistance

“…(McNamara, Lee, Lim, Lim & Roland, 2013) suggested that PfPI4K is a ubiquitous eukaryotic, lipid kinase that phosphorylates lipids to regulate intracellular signaling and trafficking (McNamara et al., ). Compound MMV390048 (2‐aminopyridine) is a new chemical class that inhibits the function of PI4K protein (Paquet, Manach, Cabrera, Younis & Henrich, ). The compound MMV390048 has showed good therapeutic activities.…”

Eine strukturelle Evaluierung medizinalchemischer Strategien gegen Wirkstoffresistenzen

“…Im Gegensatz dazu wurde kein signifikanter Effekt des PI(4)KIIIb-Inhibitors auf das frühe Ringstadium des Parasiten gefunden. Das Bipyridinderivat MMV390048 (80,A bbildung 57) ist ebenfalls ein potenter PI(4)KIIIb-Inhibitor,d er sich bereits in klinischen Studien der Phase IIa als Einzeltherapie (ClinicalTrials.gov Identifier: NCT02880241) befindet, [335] allerdings kçnnte er in der Zukunft auch in einer Kombinationstherapie mit einem Artemisininderivat verwendet werden. [333] Im Jahre 2017 evaluierten Dembele et al die Aktivitätv on KDU691 (79)g egenüber PfK13-Mutanten von mit Dihydroartemisinin vorbehandelte Parasiten im frühen Ringstadium (DP-Ring).…”