Exploring structural requirements for the inhibition of Plasmodium falciparum calcium-dependent protein kinase-4 (PfCDPK-4) using multiple in silico approaches

RSC Advances ◽  
2016 ◽  
Vol 6 (57) ◽  
pp. 51957-51982 ◽  
Author(s):  
Rahul Balasaheb Aher ◽  
Kunal Roy
Keyword(s):  
Plasmodium Falciparum ◽  
Drug Discovery ◽  
Protein Kinase ◽  
Protein Kinases ◽  
Antimalarial Drug ◽  
Dependent Protein Kinase ◽  
Structural Requirements ◽  
Calcium Dependent ◽  
Dependent Protein ◽  
Calcium Dependent Protein Kinase

Plasmodial protein kinases represent one of the most important thrust areas for antimalarial drug discovery.

scholarly journals Calcium-Dependent Protein Kinase 5 Is Required for Release of Egress-Specific Organelles in Plasmodium falciparum

mBio ◽  
2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Sabrina Absalon ◽  
Karin Blomqvist ◽  
Rachel M. Rudlaff ◽  
Travis J. DeLano ◽  
Michael P. Pollastri ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Protein Kinase ◽  
Blood Cell ◽  
Red Blood Cell ◽  
Malaria Parasite ◽  
Dependent Protein Kinase ◽  
Calcium Dependent ◽  
Dependent Protein ◽  
Parasite Egress ◽  
Calcium Dependent Protein Kinase

ABSTRACT The human malaria parasite Plasmodium falciparum requires efficient egress out of an infected red blood cell for pathogenesis. This egress event is highly coordinated and is mediated by several signaling proteins, including the plant-like P. falciparum calcium-dependent protein kinase 5 (PfCDPK5). Knockdown of PfCDPK5 results in an egress block where parasites are trapped inside their host cells. The mechanism of this PfCDPK5-dependent block, however, remains unknown. Here, we show that PfCDPK5 colocalizes with a specialized set of parasite organelles known as micronemes and is required for their discharge, implicating failure of this step as the cause of the egress defect in PfCDPK5-deficient parasites. Furthermore, we show that PfCDPK5 cooperates with the P. falciparum cGMP-dependent kinase (PfPKG) to fully activate the protease cascade critical for parasite egress. The PfCDPK5-dependent arrest can be overcome by hyperactivation of PfPKG or by physical disruption of the arrested parasite, and we show that both treatments facilitate the release of the micronemes required for egress. Our results define the molecular mechanism of PfCDPK5 function and elucidate the complex signaling pathway of parasite egress. IMPORTANCE The signs and symptoms of clinical malaria result from the replication of parasites in human blood. Efficient egress of the malaria parasite Plasmodium falciparum out of an infected red blood cell is critical for pathogenesis. The P. falciparum calcium-dependent protein kinase 5 (PfCDPK5) is essential for parasite egress. Following PfCDPK5 knockdown, parasites remain trapped inside their host cell and do not egress, but the mechanism for this block remains unknown. We show that PfCDPK5 colocalizes with parasite organelles known as micronemes. We demonstrate that PfCDPK5 is critical for the discharge of these micronemes and that failure of this step is the molecular mechanism of the parasite egress arrest. We also show that hyperactivation of the cGMP-dependent kinase PKG can overcome this arrest. Our data suggest that small molecules that inhibit the egress signaling pathway could be effective antimalarial therapeutics.

scholarly journals Targeted Inhibition of Plasmodium falciparum Calcium-Dependent Protein Kinase 1 with a Constrained J Domain-Derived Disruptor Peptide

2019 ◽  
Vol 5 (4) ◽  
pp. 506-514 ◽  
Author(s):  
Briana R. Flaherty ◽  
Tienhuei G. Ho ◽  
Sven H. Schmidt ◽  
Friedrich W. Herberg ◽  
David S. Peterson ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Protein Kinase ◽  
Dependent Protein Kinase ◽  
Calcium Dependent ◽  
Dependent Protein ◽  
J Domain ◽  
Targeted Inhibition ◽  
Calcium Dependent Protein Kinase

scholarly journals Optimization of an Imidazopyridazine Series of Inhibitors of Plasmodium falciparum Calcium-Dependent Protein Kinase 1 (PfCDPK1)

2014 ◽  
Vol 57 (8) ◽  
pp. 3570-3587 ◽  
Author(s):  
Timothy M. Chapman ◽  
Simon A. Osborne ◽  
Claire Wallace ◽  
Kristian Birchall ◽  
Nathalie Bouloc ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Protein Kinase ◽  
Dependent Protein Kinase ◽  
Calcium Dependent ◽  
Dependent Protein ◽  
Calcium Dependent Protein Kinase
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