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The gatekeeper residue and beyond: homologous calcium-dependent protein kinases as drug development targets for veterinarian Apicomplexa parasites

Published online by Cambridge University Press:  13 June 2014

KATELYN R. KEYLOUN
Affiliation:
Department of Medicine, Division of Allergy and Infectious Diseases, Center for Emerging and Re-emerging Infectious Diseases (CERID), University of Washington, Seattle, Seattle, WA, USA
MOLLY C. REID
Affiliation:
Department of Medicine, Division of Allergy and Infectious Diseases, Center for Emerging and Re-emerging Infectious Diseases (CERID), University of Washington, Seattle, Seattle, WA, USA
RYAN CHOI
Affiliation:
Department of Medicine, Division of Allergy and Infectious Diseases, Center for Emerging and Re-emerging Infectious Diseases (CERID), University of Washington, Seattle, Seattle, WA, USA
YIFAN SONG
Affiliation:
Department of Biochemistry, University of Washington, Seattle, Seattle, WA, USA
ANNA M. W. FOX
Affiliation:
Department of Medicine, Division of Allergy and Infectious Diseases, Center for Emerging and Re-emerging Infectious Diseases (CERID), University of Washington, Seattle, Seattle, WA, USA
HEIDI K. HILLESLAND
Affiliation:
Department of Medicine, Division of Allergy and Infectious Diseases, Center for Emerging and Re-emerging Infectious Diseases (CERID), University of Washington, Seattle, Seattle, WA, USA
ZHONGSHENG ZHANG
Affiliation:
Department of Biochemistry, University of Washington, Seattle, Seattle, WA, USA
RAMASUBBARAO VIDADALA
Affiliation:
Department of Chemistry, University of Washington, Seattle, Seattle, WA, USA
ETHAN A. MERRITT
Affiliation:
Department of Biochemistry, University of Washington, Seattle, Seattle, WA, USA
AUDREY O. T. LAU
Affiliation:
Veterinary Microbiology and Pathology, College of Veterinary Medicine, Washington State University, Pullman, WA, USA
DUSTIN J. MALY
Affiliation:
Department of Chemistry, University of Washington, Seattle, Seattle, WA, USA
ERKANG FAN
Affiliation:
Department of Biochemistry, University of Washington, Seattle, Seattle, WA, USA
LYNN K. BARRETT
Affiliation:
Department of Medicine, Division of Allergy and Infectious Diseases, Center for Emerging and Re-emerging Infectious Diseases (CERID), University of Washington, Seattle, Seattle, WA, USA
WESLEY C. VAN VOORHIS
Affiliation:
Department of Medicine, Division of Allergy and Infectious Diseases, Center for Emerging and Re-emerging Infectious Diseases (CERID), University of Washington, Seattle, Seattle, WA, USA
KAYODE K. OJO*
Affiliation:
Department of Medicine, Division of Allergy and Infectious Diseases, Center for Emerging and Re-emerging Infectious Diseases (CERID), University of Washington, Seattle, Seattle, WA, USA
*
*Corresponding author: Department of Medicine, Division of Allergy and Infectious Diseases, Center for Emerging and Re-emerging Infectious Diseases (CERID), University of Washington, Seattle, WA 98109, USA. E-mail: ojo67kk@u.washington.edu

Summary

Specific 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.

Type
Special Issue Article
Copyright
Copyright © Cambridge University Press 2014 

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References

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