Abstract
The single-celled apicomplexan parasite Plasmodium falciparum is responsible for the majority of deaths due to malaria each year. The selection of drug resistance has been a recurring theme over the decades with each new drug that is developed. It is therefore crucial that future generations of drugs are explored to tackle this major public health problem. Cyclic GMP (cGMP) signaling is one of the biochemical pathways that is being explored as a potential target for new antimalarial drugs. It has been shown that this pathway is essential for all of the key developmental stages of the complex malaria parasite life cycle. This gives hope that targeting cGMP signaling might give rise to drugs that treat disease, block its transmission and even prevent the establishment of infection. Here we review previous work that has been carried out to develop and optimize inhibitors of the cGMP-dependent protein kinase (PKG) which is a critical regulator of the malaria parasite life cycle.
Highlights
Malaria kills more than 400,000 people each year, mainly young children in Africa (WHO, 2019), despite the availability of effective control measures and drug treatments
One of the targets that has received significant attention in recent years is the cyclic GMP-dependent protein kinase (PKG) which is the central regulator of cGMP signaling in malaria parasites (Baker et al, 2017a; Cabrera et al, 2018)
This study provided in vivo proof of concept for PKG as an antimalarial drug target by utilizing a P. falciparum humanized SCID mouse model which demonstrated that 3 reduced blood stage parasitaemia to undetectable levels
Summary
Malaria kills more than 400,000 people each year, mainly young children in Africa (WHO, 2019), despite the availability of effective control measures and drug treatments. The selection and spread of drug resistant malaria parasites has made the development of new interventions an urgent priority so that increases in clinical cases and mortality can be avoided. One of the targets that has received significant attention in recent years is the cyclic GMP (cGMP)-dependent protein kinase (PKG) which is the central regulator of cGMP signaling in malaria parasites (Baker et al, 2017a; Cabrera et al, 2018). As cGMP reaches a threshold concentration in the cell, it binds to and activates PKG which can phosphorylate its many intracellular protein substrates. The cGMP signaling pathway is present in most organisms and controls myriad processes across the animal kingdom ranging from transducing environmental signals (Bosgraaf and Van Haastert, 2002) and mediating locomotion in some protozoa (Linder et al, 1999) to controlling cardiovascular function (Bork and Nikolaev, 2018) and regulating phototransduction in humans (Stryer, 1986)
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