Transmission of malaria to mosquitoes blocked by bumped kinase inhibitors

Kayode K. Ojo, Claudia Pfander, Natascha R. Mueller, Charlotte Burstroem, Eric T. Larson, Cassie M. Bryan, Anna M.W. Fox, Molly C. Reid, Steven M. Johnson, Ryan C. Murphy, Mark Kennedy, Henning Mann, David J. Leibly, Stephen N. Hewitt, Christophe L.M.J. Verlinde, Stefan Kappe, Ethan A. Merritt, Dustin J. Maly, Oliver Billker, Wesley C. Van Voorhis

Research output: Contribution to journalArticle

66 Scopus citations

Abstract

Effective control and eradication of malaria will require new tools to prevent transmission. Current antimalarial therapies targeting the asexual stage of Plasmodium do not prevent transmission of circulating gametocytes from infected humans to mosquitoes. Here, we describe a new class of transmission-blocking compounds, bumped kinase inhibitors (BKIs), which inhibit microgametocyte exflagellation. Oocyst formation and sporozoite production, necessary for transmission to mammals, were inhibited in mosquitoes fed on either BKI-1-treated human blood or mice treated with BKI-1. BKIs are hypothesized to act via inhibition of Plasmodium calcium-dependent protein kinase 4 and predicted to have little activity against mammalian kinases. Our data show that BKIs do not inhibit proliferation of mammalian cell lines and are well tolerated in mice. Used in combination with drugs active against asexual stages of Plasmodium, BKIs could prove an important tool for malaria control and eradication.

Original languageEnglish (US)
Pages (from-to)2301-2305
Number of pages5
JournalJournal of Clinical Investigation
Volume122
Issue number6
DOIs
StatePublished - Jun 1 2012
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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    Ojo, K. K., Pfander, C., Mueller, N. R., Burstroem, C., Larson, E. T., Bryan, C. M., Fox, A. M. W., Reid, M. C., Johnson, S. M., Murphy, R. C., Kennedy, M., Mann, H., Leibly, D. J., Hewitt, S. N., Verlinde, C. L. M. J., Kappe, S., Merritt, E. A., Maly, D. J., Billker, O., & Van Voorhis, W. C. (2012). Transmission of malaria to mosquitoes blocked by bumped kinase inhibitors. Journal of Clinical Investigation, 122(6), 2301-2305. https://doi.org/10.1172/JCI61822