Abstract
The primary effector of cGMP signaling in Plasmodium is the cGMP-dependent protein kinase (PKG). Work in human-infective Plasmodium falciparum and rodent-infective Plasmodium berghei has provided biological validation of P. falciparum PKG (PfPKG) as a drug target for treating and/or protecting against malaria. PfPKG is essential in the asexual erythrocytic and sexual cycles as well as the pre-erythrocytic cycle. Medicinal chemistry efforts, both target-based and phenotype-based, have targeted PfPKG in the past few years. This review provides a brief overview of their results and challenges.
Highlights
Specialty section: This article was submitted to Antimicrobials, Resistance and Chemotherapy, a section of the journal Frontiers in Microbiology
The primary effector of cGMP signaling in Plasmodium is the cGMP-dependent protein kinase (PKG)
Changes in intracellular levels of cGMP are converted to cellular responses through the action of effector proteins such as cGMP-dependent protein kinases [ known as protein kinase G (PKG)], cGMP-gated ion channels and cGMP binding proteins
Summary
Conditional and chemical genetics have established the essential role of PKG in the asexual cycle (Taylor et al, 2010), in the exit of merozoites from schizonts (Kim et al, 2015; Ganter et al, 2017). The net result of inhibiting PfPKG is a block in merozoite egress and interruption of the asexual cycle. In the related Apicomplexan, Toxoplasma gondii there is evidence that PKG-regulated egress of parasites is antagonized by cAMP signaling mediated by the parasite’s cAMP dependent protein kinase pathways (Jia et al, 2017). Chemical inhibition of T. gondii PKG blocks parasite egress induced through genetic downregulation of T. gondii PKA signaling. Similar interplay between PKG and PKA pathways in Plasmodium has not yet been reported P. falciparum PKA is essential for merozoite invasion (Wilde et al, 2019)
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