Erythrocyte G Protein as a Novel Target for Malarial Chemotherapy

Department of Pharmacology, Vanderbilt University, Нашвилл, Michigan, United States
PLoS Medicine (Impact Factor: 14.43). 01/2007; 3(12):e528. DOI: 10.1371/journal.pmed.0030528
Source: PubMed


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 Gs signaling blocked invasion by the human malaria parasite Plasmodium falciparum.
We investigated the erythrocyte guanine nucleotide regulatory protein Gs as a novel antimalarial target. Erythrocyte "ghosts" loaded with a Gs peptide designed to block Gs interaction with its receptors, were blocked in beta-adrenergic agonist-induced signaling. This finding directly demonstrates that erythrocyte Gs is functional and that propranolol, an antagonist of G protein-coupled beta-adrenergic receptors, dampens Gs activity in erythrocytes. We subsequently used the ghost system to directly link inhibition of host Gs 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 beta2-antagonists. beta-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 Gs antagonism offers a novel strategy to fight infection and that it has potential to be used to develop combination therapies with existing antimalarials.

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Available from: Kasturi Haldar, Dec 24, 2014
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    • "Erythrocyte invasion by Plasmodium has always been credited to parasitic mechanisms and host-cell participation regarded as passive. However, new findings highlight the importance of host-specific signaling pathways that can control parasite invasion and development (Harrison et al., 2003;Murphy et al., 2006;Saraiva et al., 2011). In this context, a multi-center study, based on genetic epidemiology, proposed an association between the occurrence of single nucleotide polymorphisms in the gene encoding the G alpha-S subunit and individual susceptibility to severe malaria, demonstrating that G-protein coupled receptor (GPCR) signaling in the host has an influence at the disease level (Auburn et al., 2008Auburn et al., , 2010). "
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    ABSTRACT: Malaria is a worldwide health problem leading the death of millions of people. The disease is induced by different species of protozoa parasites from the genus Plasmodium. In humans, Plasmodium falciparum is the most dangerous species responsible for severe disease. Despite all efforts to establish the pathogenesis of malaria, it is far from being fully understood. In addition, resistance to existing drugs has developed in several strains and the development of new effective compounds to fight these parasites is a major issue. Recent discoveries indicate the potential role of the renin-angiotensin system (RAS) in malaria infection. Angiotensin receptors have not been described in the parasite genome, however several reports in the literature suggest a direct effect of angiotensin-derived peptides on different aspects of the host-parasite interaction. The aim of this review is to highlight new findings on the involvement of the RAS in parasite development and in the regulation of the host immune response in an attempt to expand our knowledge of the pathogenesis of this disease.
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    • "Ga subunits, components of heterotrimeric G proteins that interact with G protein coupled receptors to transduce signals from the membrane, are found in erythrocyte lipid rafts and within the PVM (Lauer et al, 2000). G protein coupled receptor signalling, through the b 2 -adrenergic receptor , is required for merozoite entry into erythrocytes, providing a possible explanation for the role of lipid rafts in malaria parasite invasion (Harrison et al, 2003; Murphy et al, 2006). A more indirect link between parasite invasion and signalling to the erythrocyte cytoskeleton is provided by studies on extracellular ligand binding to erythrocyte transmembrane proteins, especially those that are known receptors for merozoite invasion (Cowman & Crabb, 2006; Gaur et al, 2004). "

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    • "Recent research has identified an essential role for host erythrocyte enzymes in parasite development [51,52]. A number of the parasiticidal compounds may target a host cell enzyme rather than a molecule encoded by the parasite. "
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