Erythrocyte G Protein as a Novel Target for Malarial Chemotherapy

BACKGROUND: 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. METHODS AND FINDINGS: 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 β(2)-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. CONCLUSIONS: 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

The safety of amodiaquine use in pregnant women.

Few antimalarial drugs have been evaluated extensively in pregnancy because of fears over toxicity. However, increasing Plasmodium falciparum resistance to chloroquine and sulfadoxine-pyrimethamine makes finding alternative antimalarials that are safe and effective in pregnancy a priority. There is a renewed interest in amodiaquine as a potential candidate, particularly as a partner drug in artemisinin-based combination therapy. The available data suggest that, at standard dosages, amodiaquine is not teratogenic and that the adverse events associated with taking amodiaquine in pregnancy are not greater than those associated with falciparum malaria in pregnancy. Thus, amodiaquine in combination with other antimalarial drugs may be useful for malaria treatment in pregnancy, but inadequate data on its safety and pharmacokinetics in pregnancy limits its deployment for intermittent preventive treatment in pregnancy