Extended-spectrum antiprotozoal bumped kinase inhibitors: A review

Wesley C. Van Voorhis; J. Stone Doggett; Marilyn Parsons; Matthew A. Hulverson; Ryan Choi; Samuel L.M. Arnold; Michael W. Riggs; Andrew Hemphill; Daniel K. Howe; Robert H. Mealey; Audrey O.T. Lau; Ethan A. Merritt; Dustin J. Maly; Erkang Fan; Kayode K. Ojo

doi:10.1016/j.exppara.2017.01.001

Extended-spectrum antiprotozoal bumped kinase inhibitors: A review

Wesley C. Van Voorhis
, J. Stone Doggett
, Marilyn Parsons
, Matthew A. Hulverson
, Ryan Choi
, Samuel L.M. Arnold
, Michael W. Riggs
, Andrew Hemphill
, Daniel K. Howe
, Robert H. Mealey
, Audrey O.T. Lau
, Ethan A. Merritt
, Dustin J. Maly
, Erkang Fan
, Kayode K. Ojo

Research output: Contribution to journal › Article › peer-review

59 Scopus citations

Abstract

Many life-cycle processes in parasites are regulated by protein phosphorylation. Hence, disruption of essential protein kinase function has been explored for therapy of parasitic diseases. However, the difficulty of inhibiting parasite protein kinases to the exclusion of host orthologues poses a practical challenge. A possible path around this difficulty is the use of bumped kinase inhibitors for targeting calcium-dependent protein kinases that contain atypically small gatekeeper residues and are crucial for pathogenic apicomplexan parasites' survival and proliferation. In this article, we review efficacy against the kinase target, parasite growth in vitro, and in animal infection models, as well as the relevant pharmacokinetic and safety parameters of bumped kinase inhibitors.

Original language	English
Pages (from-to)	71-83
Number of pages	13
Journal	Experimental Parasitology
Volume	180
DOIs	https://doi.org/10.1016/j.exppara.2017.01.001
State	Published - Sep 2017

Bibliographical note

Publisher Copyright:
© 2017 Elsevier Inc.

Funding

This work was supported by the US National Institutes of Health (NICHHD R01HD080670 & NIAID R01AI111341, R01AI089441) and the USDA (2014-06183). This work was also supported by Swiss National Science Foundation (grant No. 310030_165782) and in part by Career Development Award # BX002440 to J. Stone Doggett from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development.

Funders	Funder number
United States Department of Veterans Affairs Biomedical Laboratory Research and Development Program
NIH National Institute of Child Health and Human Development National Center for Medical Rehabilitation Research
National Institutes of Health (NIH)
NICHHD	R01HD080670
National Institute of Allergy and Infectious F32-AI286447 Cydney N. Johnson Diseases National Institute of Allergy and Infectious R01AI168214 Jason W. Rosch Diseases National Institute of Allergy and Infectious P30 Cydney N. Johnson Diseases National Institute of Allergy and Infectious R00-AI166116 Christopher D. Radka Diseases National Institute of Allergy and Infectious T32-AI106700 Cydney N. Johnson Diseases National Institute of Allergy and Infectious R01AI192221 Jason W. Rosch Diseases National Inst...	R01AI089441, R01AI111341, R21AI127493
U.S. Department of Agriculture	2014-06183
Eunice Kennedy Shriver National Institute of Child Health and Human Development	R01HD080670
U.S. Department of Veterans Affairs	IK2BX002440
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung	BX002440, 165782, 310030_165782

Keywords

Bumped kinase inhibitors
Calcium-dependent protein kinase
Gatekeeper residue

ASJC Scopus subject areas

Parasitology
Immunology
Infectious Diseases

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.exppara.2017.01.001

Cite this

Van Voorhis, W. C., Doggett, J. S., Parsons, M., Hulverson, M. A., Choi, R., Arnold, S. L. M., Riggs, M. W., Hemphill, A., Howe, D. K., Mealey, R. H., Lau, A. O. T., Merritt, E. A., Maly, D. J., Fan, E., & Ojo, K. K. (2017). Extended-spectrum antiprotozoal bumped kinase inhibitors: A review. Experimental Parasitology, 180, 71-83. https://doi.org/10.1016/j.exppara.2017.01.001

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abstract = "Many life-cycle processes in parasites are regulated by protein phosphorylation. Hence, disruption of essential protein kinase function has been explored for therapy of parasitic diseases. However, the difficulty of inhibiting parasite protein kinases to the exclusion of host orthologues poses a practical challenge. A possible path around this difficulty is the use of bumped kinase inhibitors for targeting calcium-dependent protein kinases that contain atypically small gatekeeper residues and are crucial for pathogenic apicomplexan parasites' survival and proliferation. In this article, we review efficacy against the kinase target, parasite growth in vitro, and in animal infection models, as well as the relevant pharmacokinetic and safety parameters of bumped kinase inhibitors.",

keywords = "Bumped kinase inhibitors, Calcium-dependent protein kinase, Gatekeeper residue",

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month = sep,

doi = "10.1016/j.exppara.2017.01.001",

language = "English",

volume = "180",

pages = "71--83",

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AU - Van Voorhis, Wesley C.

AU - Doggett, J. Stone

AU - Parsons, Marilyn

AU - Hulverson, Matthew A.

AU - Choi, Ryan

AU - Arnold, Samuel L.M.

AU - Riggs, Michael W.

AU - Hemphill, Andrew

AU - Howe, Daniel K.

AU - Mealey, Robert H.

AU - Lau, Audrey O.T.

AU - Merritt, Ethan A.

AU - Maly, Dustin J.

AU - Fan, Erkang

AU - Ojo, Kayode K.

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AB - Many life-cycle processes in parasites are regulated by protein phosphorylation. Hence, disruption of essential protein kinase function has been explored for therapy of parasitic diseases. However, the difficulty of inhibiting parasite protein kinases to the exclusion of host orthologues poses a practical challenge. A possible path around this difficulty is the use of bumped kinase inhibitors for targeting calcium-dependent protein kinases that contain atypically small gatekeeper residues and are crucial for pathogenic apicomplexan parasites' survival and proliferation. In this article, we review efficacy against the kinase target, parasite growth in vitro, and in animal infection models, as well as the relevant pharmacokinetic and safety parameters of bumped kinase inhibitors.

KW - Bumped kinase inhibitors

KW - Calcium-dependent protein kinase

KW - Gatekeeper residue

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Extended-spectrum antiprotozoal bumped kinase inhibitors: A review

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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