scholarly journals Plasmodium falciparum cGMP-Dependent Protein Kinase – A Novel Chemotherapeutic Target

2021 ◽  
Vol 11 ◽  
Author(s):  
David Rotella ◽  
John Siekierka ◽  
Purnima Bhanot
Keyword(s):  
Plasmodium Falciparum ◽  
Protein Kinase ◽  
Drug Target ◽  
Dependent Protein Kinase ◽  
The Past ◽  
Cgmp Dependent Protein Kinase ◽  
Cgmp Signaling ◽  
Erythrocytic Cycle ◽  
Dependent Protein ◽  
Primary Effector

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.

scholarly journals Mechanism of Allosteric Inhibition of Plasmodium falciparum CGMP-Dependent Protein Kinase

2020 ◽  
Vol 118 (3) ◽  
pp. 522a
Author(s):  
Olivia Byun ◽  
Katherine Van ◽  
Philipp Henning ◽  
Friedrich W. Herberg ◽  
Giuseppe Melacini
Keyword(s):  
Plasmodium Falciparum ◽  
Protein Kinase ◽  
Dependent Protein Kinase ◽  
Allosteric Inhibition ◽  
Cgmp Dependent Protein Kinase ◽  
Dependent Protein

scholarly journals The role of a parasite-specific D-site in activation of Plasmodium falciparum cGMP-dependent protein kinase

2015 ◽  
Vol 16 (S1) ◽  
Author(s):  
Eugen Franz ◽  
Jeong Joo Kim ◽  
Olga Schneider ◽  
Daniela Bertinetti ◽  
Choel Kim ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Protein Kinase ◽  
Dependent Protein Kinase ◽  
Cgmp Dependent Protein Kinase ◽  
Dependent Protein

scholarly journals Spatiotemporal and Functional Characterisation of the Plasmodium falciparum cGMP-Dependent Protein Kinase

PLoS ONE ◽  
2012 ◽  
Vol 7 (11) ◽  
pp. e48206 ◽  
Author(s):  
Christine S. Hopp ◽  
Christian Flueck ◽  
Lev Solyakov ◽  
Andrew Tobin ◽  
David A. Baker
Keyword(s):  
Plasmodium Falciparum ◽  
Protein Kinase ◽  
Dependent Protein Kinase ◽  
Cgmp Dependent Protein Kinase ◽  
Functional Characterisation ◽  
Dependent Protein

scholarly journals Mechanism of allosteric inhibition in the Plasmodium falciparum cGMP-dependent protein kinase

2020 ◽  
Vol 295 (25) ◽  
pp. 8480-8491 ◽  
Author(s):  
Jung Ah Byun ◽  
Katherine Van ◽  
Jinfeng Huang ◽  
Philipp Henning ◽  
Eugen Franz ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Protein Kinase ◽  
Rational Design ◽  
Kinase Inhibitors ◽  
Inhibition Mechanism ◽  
Dependent Protein Kinase ◽  
Cgmp Dependent Protein Kinase ◽  
Cgmp Analog ◽  
Dependent Protein ◽  
Intermediate Surface

Most malaria deaths are caused by the protozoan parasite Plasmodium falciparum. Its life cycle is regulated by a cGMP-dependent protein kinase (PfPKG), whose inhibition is a promising antimalaria strategy. Allosteric kinase inhibitors, such as cGMP analogs, offer enhanced selectivity relative to competitive kinase inhibitors. However, the mechanisms underlying allosteric PfPKG inhibition are incompletely understood. Here, we show that 8-NBD-cGMP is an effective PfPKG antagonist. Using comparative NMR analyses of a key regulatory domain, PfD, in its apo, cGMP-bound, and cGMP analog–bound states, we elucidated its inhibition mechanism of action. Using NMR chemical shift analyses, molecular dynamics simulations, and site-directed mutagenesis, we show that 8-NBD-cGMP inhibits PfPKG not simply by reverting a two-state active versus inactive equilibrium, but by sampling also a distinct inactive “mixed” intermediate. Surface plasmon resonance indicates that the ability to stabilize a mixed intermediate provides a means to effectively inhibit PfPKG, without losing affinity for the cGMP analog. Our proposed model may facilitate the rational design of PfPKG-selective inhibitors for improved management of malaria.

scholarly journals Targeting the Malaria Parasite cGMP-Dependent Protein Kinase to Develop New Drugs

2020 ◽  
Vol 11 ◽  
Author(s):  
David A. Baker ◽  
Alexios N. Matralis ◽  
Simon A. Osborne ◽  
Jonathan M. Large ◽  
Maria Penzo
Keyword(s):  
Life Cycle ◽  
Protein Kinase ◽  
Malaria Parasite ◽  
Public Health Problem ◽  
Major Public Health Problem ◽  
Parasite Life Cycle ◽  
Dependent Protein Kinase ◽  
Cgmp Dependent Protein Kinase ◽  
Cgmp Signaling ◽  
Dependent Protein

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.

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