scholarly journals Calcium-dependent Protein Kinases in Malaria Parasite Development and Infection

2020 ◽  
Vol 29 ◽  
pp. 096368971988488 ◽  
Author(s):  
George Ghartey-Kwansah ◽  
Qinan Yin ◽  
Zhongguang Li ◽  
Kristyn Gumpper ◽  
Yuting Sun ◽  
...  

Apicomplexan parasites have challenged researchers for nearly a century. A major challenge to developing efficient treatments and vaccines is the parasite’s ability to change its cellular and molecular makeup to develop intracellular and extracellular niches in its hosts. Ca2+ signaling is an important messenger for the egress of the malaria parasite from the infected erythrocyte, gametogenesis, ookinete motility in the mosquito, and sporozoite invasion of mammalian hepatocytes. Calcium-dependent protein kinases (CDPKs) have crucial functions in calcium signaling at various stages of the parasite’s life cycle; this therefore makes them attractive drug targets against malaria. Here, we summarize the functions of the various CDPK isoforms in relation to the malaria life cycle by emphasizing the molecular mechanism of developmental progression within host tissues. We also discuss the current development of anti-malarial drugs, such as how specific bumped kinase inhibitors (BKIs) for parasite CDPKs have been shown to reduce infection in Toxoplasma gondii, Cryptosporidium parvum, and Plasmodium falciparum. Our suggested combinations of BKIs, artemisinin derivatives with peroxide bridge, and inhibitors on the Ca(2+)-ATPase PfATP6 as a potential target should be inspected further as a treatment against malaria.

Parasitology ◽  
2014 ◽  
Vol 141 (11) ◽  
pp. 1499-1509 ◽  
Author(s):  
KATELYN R. KEYLOUN ◽  
MOLLY C. REID ◽  
RYAN CHOI ◽  
YIFAN SONG ◽  
ANNA M. W. FOX ◽  
...  

SUMMARYSpecific roles of individual CDPKs vary, but in general they mediate essential biological functions necessary for parasite survival. A comparative analysis of the structure-activity relationships (SAR) of Neospora caninum, Eimeria tenella and Babesia bovis calcium-dependent protein kinases (CDPKs) together with those of Plasmodium falciparum, Cryptosporidium parvum and Toxoplasma gondii was performed by screening against 333 bumped kinase inhibitors (BKIs). Structural modelling and experimental data revealed that residues other than the gatekeeper influence compound–protein interactions resulting in distinct sensitivity profiles. We subsequently defined potential amino-acid structural influences within the ATP-binding cavity for each orthologue necessary for consideration in the development of broad-spectrum apicomplexan CDPK inhibitors. Although the BKI library was developed for specific inhibition of glycine gatekeeper CDPKs combined with low inhibition of threonine gatekeeper human SRC kinase, some library compounds exhibit activity against serine- or threonine-containing CDPKs. Divergent BKI sensitivity of CDPK homologues could be explained on the basis of differences in the size and orientation of the hydrophobic pocket and specific variation at other amino-acid positions within the ATP-binding cavity. In particular, BbCDPK4 and PfCDPK1 are sensitive to a larger fraction of compounds than EtCDPK1 despite the presence of a threonine gatekeeper in all three CDPKs.


2018 ◽  
Vol 34 (2) ◽  
pp. 259-265 ◽  
Author(s):  
Hemant B Kardile ◽  
◽  
Vikrant ◽  
Nirmal Kant Sharma ◽  
Ankita Sharma ◽  
...  

2007 ◽  
Vol 19 (10) ◽  
pp. 3019-3036 ◽  
Author(s):  
Sai-Yong Zhu ◽  
Xiang-Chun Yu ◽  
Xiao-Jing Wang ◽  
Rui Zhao ◽  
Yan Li ◽  
...  

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