Identification and testing of inhibitors of kinases secreted from malaria parasites

Abstract

Small molecule inhibitors of a family of secreted kinases from the malaria parasite Plasmodium falciparum were identified and shown to arrest parasite growth in blood culture. P. falciparum is primarily an intracellular parasite in its human host. During the blood stage of a malaria infection, the parasite dramatically alters the surface of its host red blood cell, by exporting proteins (accounting for roughly 10% of its genome) into the erythrocyte. Among these proteins is a family of 18 secreted Ser/Thr kinases. Recombinant expression of a number of these kinases and their Plasmodium vivax ortholog has permitted the screening of a library of potential kinase inhibitors. Several of these compounds were found to attenuate kinase activity in vitro. In order to ascertain whether inhibiting kinase activity affects the ability of parasites to remodel the red blood cell surface, the five best inhibitors were incubated with parasites in human blood culture. Scanning electron microscopy was used to assess the extent of red blood cell surface remodeling. Rather than an overt effect on remodeling, initial results showed an overall growth arrest of treated parasites, with no progression to trophozoites in the treated cultures.Support or Funding InformationAmerican Philosophical Society Franklin Research Grant