A Specific Inhibitor of PfCDPK4 Blocks Malaria Transmission: Chemical-genetic Validation

Overview

Journal J Infect Dis

Publisher Oxford University Press

Specialty Infectious Diseases

Date 2013 Oct 15

PMID 24123773

Citations 57

Authors

Kayode K Ojo

Richard T Eastman

RamaSubbaRao Vidadala

Zhongsheng Zhang

Kasey L Rivas

Ryan Choi

Justin D Lutz

Molly C Reid

Anna M W Fox

Matthew A Hulverson

Mark Kennedy

Nina Isoherranen

Laura M Kim

Kenneth M Comess

Dale J Kempf

Christophe L M J Verlinde

Xin-Zhuan Su

Stefan H I Kappe

Dustin J Maly

Erkang Fan

Wesley C Van Voorhis

Affiliations

Soon will be listed here.

Abstract

Malaria parasites are transmitted by mosquitoes, and blocking parasite transmission is critical in reducing or eliminating malaria in endemic regions. Here, we report the pharmacological characterization of a new class of malaria transmission-blocking compounds that acts via the inhibition of Plasmodia CDPK4 enzyme. We demonstrate that these compounds achieved selectivity over mammalian kinases by capitalizing on a small serine gatekeeper residue in the active site of the Plasmodium CDPK4 enzyme. To directly confirm the mechanism of action of these compounds, we generated P. falciparum parasites that express a drug-resistant methionine gatekeeper (S147 M) CDPK4 mutant. Mutant parasites showed a shift in exflagellation EC50 relative to the wild-type strains in the presence of compound 1294, providing chemical-genetic evidence that CDPK4 is the target of the compound. Pharmacokinetic analyses suggest that coformulation of this transmission-blocking agent with asexual stage antimalarials such as artemisinin combination therapy (ACT) is a promising option for drug delivery that may reduce transmission of malaria including drug-resistant strains. Ongoing studies include refining the compounds to improve efficacy and toxicological properties for efficient blocking of malaria transmission.

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