title: A specific inhibitor of PfCDPK4 blocks malaria transmission: chemical-genetic validation.
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.
authors.affiliation: Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle.
authors.forename: Kayode K
authors.initials: KK
authors.lastname: Ojo
authors.forename: Richard T
authors.initials: RT
authors.lastname: Eastman
authors.forename: Ramasubbarao
authors.initials: R
authors.lastname: Vidadala
authors.forename: Zhongsheng
authors.initials: Z
authors.lastname: Zhang
authors.forename: Kasey L
authors.initials: KL
authors.lastname: Rivas
authors.forename: Ryan
authors.initials: R
authors.lastname: Choi
authors.forename: Justin D
authors.initials: JD
authors.lastname: Lutz
authors.forename: Molly C
authors.initials: MC
authors.lastname: Reid
authors.forename: Anna M W
authors.initials: AM
authors.lastname: Fox
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Hulverson
authors.forename: Mark
authors.initials: M
authors.lastname: Kennedy
authors.forename: Nina
authors.initials: N
authors.lastname: Isoherranen
authors.forename: Laura M
authors.initials: LM
authors.lastname: Kim
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Comess
authors.forename: Dale J
authors.initials: DJ
authors.lastname: Kempf
authors.forename: Christophe L M J
authors.initials: CL
authors.lastname: Verlinde
authors.forename: Xin-Zhuan
authors.initials: XZ
authors.lastname: Su
authors.forename: Stefan H I
authors.initials: SH
authors.lastname: Kappe
authors.forename: Dustin J
authors.initials: DJ
authors.lastname: Maly
authors.forename: Erkang
authors.initials: E
authors.lastname: Fan
authors.forename: Wesley C
authors.initials: WC
authors.lastname: Van Voorhis
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000302:isolation & purification / Q000378:metabolism* / Q000493:pharmacokinetics; D004791:Enzyme Inhibitors / Q000302:isolation & purification / Q000378:metabolism* / Q000493:pharmacokinetics; D005407:Flagella / Q000187:drug effects / Q000502:physiology; D051379:Mice; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000502:physiology; D011494:Protein Kinases / Q000378:metabolism*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors*; D017871:Calcium-Calmodulin-Dependent Protein Kinases
chemical_list: D000962:Antimalarials; D004791:Enzyme Inhibitors; D011494:Protein Kinases; D015800:Protozoan Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases
keywords: Plasmodium falciparum; bumped kinase inhibitors; calcium-dependent protein kinase 4; malaria transmission-blocking