Small molecule plasmodium FKBP35 inhibitor as a potential antimalaria agent

Abstract

Malaria parasite strains have emerged to tolerate the therapeutic effects of the prophylactics and drugs presently available. This resistance now poses a serious challenge to researchers in the bid to overcome malaria parasitic infection. Recent studies have shown that FK520 and its analogs inhibit malaria parasites growth by binding to FK506 binding proteins (FKBPs) of the parasites. Structure based drug screening efforts based on three-dimensional structural information of FKBPs from Plasmodium falciparum led us to identify new chemical entities that bind to the parasite FKBP35 and inhibit its growth. Our experimental results verify that this novel compound (D44) modulate the PPIase activity of Plasmodium FKBP35 and demonstrate the stage-specific growth inhibition of Plasmodium falciparum strains. Here, we present the X-ray crystallographic structures of FK506 binding domains (FKBDs) of PfFKBP35 and PvFKBP35 in complex with the newly identified inhibitor providing molecular insights into its mode of action.