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A specific inhibitor of PfCDPK4 blocks malaria transmission: Chemical-genetic validation.
Title | A specific inhibitor of PfCDPK4 blocks malaria transmission: Chemical-genetic validation. |
Publication Type | Journal Article |
Year of Publication | 2013 |
Authors | Ojo, KK, Eastman, RT, Vidadala, R, Zhang, Z, Rivas, KL, Choi, R, Lutz, JD, Reid, MC, Fox, AMW, Hulverson, MA, Kennedy, M, Isoherranen, N, Kim, LM, Comess, KM, Kempf, DJ, Verlinde, CLMJ, Su, X-Z, Kappe, S, Maly, DJ, Fan, E, Van Voorhis, WC |
Journal | J Infect Dis |
Date Published | 2013 Oct 10 |
ISSN | 1537-6613 |
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 (S147M) 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 co-formulation of this transmission-blocking agent with asexual stage anti-malarias 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. |
DOI | 10.1093/infdis/jit522 |
Alternate Journal | J. Infect. Dis. |
PubMed ID | 24123773 |