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

Ojo, Kayode K.; Eastman, Richard T.; Vidadala, RamaSubbaRao; Zhang, Zhongsheng; Rivas, Kasey L.; Choi, Ryan; Lutz, Justin D.; Reid, Molly C.; Fox, Anna M. W.; Hulverson, Matthew A.; Kennedy, Mark; Isoherranen, Nina; Kim, Laura M.; Comess, Kenneth M.; Kempf, Dale J.; Verlinde, Christophe L. M. J.; Su, Xin-zhuan; Kappe, Stefan H. I.; Maly, Dustin J.; Fan, Erkang
January 2014
Journal of Infectious Diseases;Jan2014, Vol. 209 Issue 2, p275
Academic Journal
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 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.


Related Articles

  • Reducing Plasmodium falciparum Malaria Transmission in Africa: A Model-Based Evaluation of Intervention Strategies. Griffin, Jamie T.; Hollingsworth, T. Deirdre; Okell, Lucy C.; Churcher, Thomas S.; White, Michael; Hinsley, Wes; Bousema, Teun; Drakeley, Chris J.; Ferguson, Neil M.; Basáñez, María-Gloria; Ghani, Azra C. // PLoS Medicine;Aug2010, Vol. 7 Issue 8, p1 

    Background: Over the past decade malaria intervention coverage has been scaled up across Africa. However, it remains unclear what overall reduction in transmission is achievable using currently available tools. Methods and Findings: We developed an individual-based simulation model for...

  • Malaria bug gives mosquitoes a super-sharp sense of smell.  // New Scientist;5/25/2013, Vol. 218 Issue 2918, p17 

    The article discusses a report published in "PLoS One" by researcher James Logan and team on malaria-transmitting Anopheles gambiae mosquitoes, finding that mosquitoes infected with Plasmodium falciparum malaria parasites had stronger responses to human smells and were more likely to bite humans.

  • Modeling Within-Host Effects of Drugs on Plasmodium falciparum Transmission and Prospects for Malaria Elimination. Johnston, Geoffrey L.; Gething, Peter W.; Hay, Simon I.; Smith, David L.; Fidock, David A. // PLoS Computational Biology;Jan2014, Vol. 10 Issue 1, p1 

    Achieving a theoretical foundation for malaria elimination will require a detailed understanding of the quantitative relationships between patient treatment-seeking behavior, treatment coverage, and the effects of curative therapies that also block Plasmodium parasite transmission to mosquito...

  • Large-scale spraying of bednets to control mosquito vectors and malaria in Sichuan, China. Huailu, Cheng; Wen, Yang // Bulletin of the World Health Organization;1995, Vol. 73 Issue 3, p321 

    Reports on the spraying of bednets owned by rural householders in Sichuan Province, China since 1987 with deltamethrin to control mosquito vectors and malaria. Indications of reductions in biting populations and survival of two vector species based on 1987-89 data; Mortality rate data based on...

  • Malaria may be on move to `tropical' Canada. Wilton, Peter // CMAJ: Canadian Medical Association Journal;01/27/98, Vol. 158 Issue 2, p160 

    Focuses on the occurrence of malaria in Canada. The number of confirmed cases in 1996; The factors necessary for an outbreak of malaria, including the Anopheles mosquito; Mention of the possible effect of global warming.

  • Public health: Malaria mosquito lurks outdoors.  // Nature;2/10/2011, Vol. 470 Issue 7333, p142 

    The article focuses on the discovery of a new subgroup of malaria carrying mosquito, in which it explains why malaria obliteration efforts obtain limited success.

  • The DEADLIEST Creature on Earth.  // Scholastic Action;10/26/2015, Vol. 39 Issue 3, p2 

    The article offers information on mosquitoes which kill more than half a million people annually, how mosquitoes bite, and the efforts being done to stamp out diseases spread by mosquitoes such as malaria.

  • Serology describes a profile of declining malaria transmission in Farafenni, The Gambia. van den Hoogen, Lotus L.; Griffin, Jamie T.; Cook, Jackie; Sepúlveda, Nuno; Corran, Patrick; Conway, David J.; Milligan, Paul; Affara, Muna; Allen, Stephen J.; Proietti, Carla; Ceesay, Serign J.; Targett, Geoffrey A.; D'Alessandro, Umberto; Greenwood, Brian; Riley, Eleanor M.; Drakeley, Chris // Malaria Journal;10/22/2015, Vol. 14 Issue 1, p1 

    Background: Malaria morbidity and mortality has declined in recent years in a number of settings. The ability to describe changes in malaria transmission associated with these declines is important in terms of assessing the potential effects of control interventions, and for monitoring and...

  • Taking a Bite Out of Mosquitoes: A New Drug to Block Transmission of Malaria. Durvasula, Ravi // Journal of Infectious Diseases;Jan2014, Vol. 209 Issue 2, p177 

    The author reflects on the development of new drugs and strategies to control the transmission of malaria with reference of the study "Specific inhibitor of PfCDPK4 blocks malaria transmission: Chemical-genetic validation" by K. K. Ojo and colleagues, published within the issue of as of January...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics