Identification of potent and selectiveN-myristoyltransferase inhibitors ofPlasmodium vivaxliver stage hypnozoites and schizonts

Abstract

ABSTRACTNew drugs targeting multiple stages of the malaria-causing parasite,Plasmodium, are needed to reduce and eliminate malaria worldwide.N-Myristoyltransferase (NMT) is an essential eukaryotic enzyme, and a validated chemically tractable drug target for malaria. Previous efforts have failed to target NMT owing to the low selectivity for thePlasmodiumenzyme compared with human NMTs. Herein, we applied a structure-guided approach using previously reported NMT inhibitors as scaffolds to develop a new generation ofPlasmodium vivaxNMT (PvNMT) targeting compounds. We report a series of compounds with IC50values in the nM range and an order of magnitude improved selectivity toPlasmodiumNMT over human NMT (HsNMT). X-ray co-crystallization ofPvNMT with a representative lead compound,12b, supported the prevailing hypothesis that a conformational difference in a key tyrosine residue ofPvNMT andHsNMT drives the selectivity between these enzymes. The compounds were triaged based on their selectivity forPvNMT. They significantly decreasedP. falciparumblood-stage parasite load, with IC50values ranging from 0.36 μM to 1.25 μM. The compounds exhibited a dose-dependent inhibition ofP. vivaxliver stage schizont and hypnozoite infection, consistently, in three differentP. vivaxisolates with IC50values ranging from 2.2 μM to 6 μM and from 1.2 μM to 12 μM. Our data provide evidence that NMT inhibitors could be multistage antimalarials, targeting both dormant and developing liver stage parasites, which is essential for malaria elimination.One Sentence SummaryPotent and selectiveN-myristoyltransferase inhibitors ofPlasmodium vivaxhypnozoites and schizonts were synthesized and tested.