Erythrocyte G Protein as a Novel Target for Malarial Chemotherapy

Abstract

Malaria remains a serious health problem because resistance develops to all currently used drugs when their parasite targets mutate. Novel antimalarial drug targets are urgently needed to reduce global morbidity and mortality. Our prior results suggested that inhibiting erythrocyte G_s signaling blocked invasion by the human malaria parasite Plasmodium falciparum. We investigated the erythrocyte guanine nucleotide regulatory protein G_s as a novel antimalarial target. Erythrocyte “ghosts” loaded with a G_s peptide designed to block G_s interaction with its receptors, were blocked in β-adrenergic agonist-induced signaling. This finding directly demonstrates that erythrocyte G_s is functional and that propranolol, an antagonist of G protein–coupled β-adrenergic receptors, dampens G_s activity in erythrocytes. We subsequently used the ghost system to directly link inhibition of host G_s to parasite entry. In addition, we discovered that ghosts loaded with the peptide were inhibited in intracellular parasite maturation. Propranolol also inhibited blood-stage parasite growth, as did other β₂-antagonists. β-blocker growth inhibition appeared to be due to delay in the terminal schizont stage. When used in combination with existing antimalarials in cell culture, propranolol reduced the 50% and 90% inhibitory concentrations for existing drugs against P. falciparum by 5- to 10-fold and was also effective in reducing drug dose in animal models of infection. Together these data establish that, in addition to invasion, erythrocyte G protein signaling is needed for intracellular parasite proliferation and thus may present a novel antimalarial target. The results provide proof of the concept that erythrocyte G_s antagonism offers a novel strategy to fight infection and that it has potential to be used to develop combination therapies with existing antimalarials.