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Main ARTICLEA Particular Inhibitor of PfCDPK4 Blocks Malaria Transmission: Chemical-genetic ValidationKayode K. Ojo,1 Richard T. Eastman,2 RamaSubbaRao Vidadala,three Zhongsheng Zhang,4 Kasey L. Rivas,1 Ryan Choi,1 Justin D. Lutz,five Molly C. Reid,1 Anna M. W. Fox,1 Matthew A. Hulverson,1 Mark Kennedy,6 Nina Isoherranen,5 Laura M. Kim,7 Kenneth M. Comess,7 Dale J. Kempf,7 Christophe L. M. J. Verlinde,4 Xin-zhuan Su,2 Stefan H.I. Kappe,five Dustin J. Maly,3 Erkang Fan,4 and Wesley C. Van VoorhisDivision of Allergy and Infectious Illnesses, Department of Medicine, University of Washington, Seattle; 2Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Ailments, National Institutes of Health, Bethesda, Maryland; 3Department of Chemistry, 4Department of Biochemistry, and 5Department of Pharmaceutics, University of Washington, Seattle; 6Seattle Biomedical Investigation Institute, Washington; and 7Global Pharmaceutical R D, AbbVie, North Chicago, Illinois(See the editorial commentary by Durvasula on pages 177.Acetazolamide )Malaria parasites are transmitted by mosquitoes, and blocking parasite transmission is important in minimizing or eliminating malaria in endemic regions.Pentamidine isethionate Here, we report the pharmacological characterization of a new class of malaria transmission-blocking compounds that acts via the inhibition of Plasmodia CDPK4 enzyme.PMID:23376608 We demonstrate that these compounds achieved selectivity over mammalian kinases by capitalizing on a little serine gatekeeper residue in the active site on the Plasmodium CDPK4 enzyme. To straight confirm the mechanism of action of these compounds, we generated P. falciparum parasites that express a drug-resistant methionine gatekeeper (S147M) CDPK4 mutant. Mutant parasites showed a shift in exflagellation EC50 relative to the wild-type strains within the presence of compound 1294, delivering chemical-genetic proof that CDPK4 will be the target of the compound. Pharmacokinetic analyses suggest that coformulation of this transmission-blocking agent with asexual stage antimalarials like artemisinin combination therapy (ACT) is often a promising option for drug delivery that may possibly reduce transmission of malaria which includes drug-resistant strains. Ongoing studies contain refining the compounds to improve efficacy and toxicological properties for effective blocking.
