Antimalarial and Plasmodium falciparum serpentine receptor 12 targeting effect of a purinergic receptor antagonist FDA approved drug

Abstract

Intraerythrocytic stages of Plasmodium falciparum responsible for all clinical manifestations of malaria are regulated by array of signaling cascades and effector molecules that represents attractive targets for antimalarial therapy. G-protein coupled receptors (GPCRs) are druggable targets in treatment of various pathological conditions however there is limited understanding about the role of GPCRs in malaria pathogenesis. In Plasmodium, serpentine receptors (PfSR1, PfSR10, PfSR12 and PfSR25) with GPCR like membrane topology have been reported with the finite knowledge about their potential as antimalarial targets. Herein we evaluated the druggability of PfSR12 using FDA approved P2Y type of purinergic signaling antagonist, Prasugrel. Blocking of purinergic receptor signaling resulted in inhibition of growth and development of P. falciparum. Progression studies indicated the inhibitory effect of purinergic signalling inhibitor begins in late erythrocyte stages predominantly in the schizonts. Furthermore, purinoreceptor inhibitor blocked in vivo growth of malaria parasite in mouse experimental model. The localization of PfSR1, PfSR10, PfSR12 and PfSR25 was analyzed by immunofluorescence assays. The putative purinergic receptor PfSR12 is found to be expressed in late intraerythrocytic stages. Prasugrel, a generic purinoreceptor inhibitor and agonist ATP showed specific binding to recombinant PfSR12 confirming it as purinergic receptor. This study indicates the presence of P2Y type of purinergic signaling in growth and development of malaria parasite and suggests PfSR12 as putative purinergic receptor.