title: Transmission of malaria to mosquitoes blocked by bumped kinase inhibitors.
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.
authors.affiliation: Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, Washington 98195-6423, USA.
authors.forename: Kayode K
authors.initials: KK
authors.lastname: Ojo
authors.forename: Claudia
authors.initials: C
authors.lastname: Pfander
authors.forename: Natascha R
authors.initials: NR
authors.lastname: Mueller
authors.forename: Charlotte
authors.initials: C
authors.lastname: Burstroem
authors.forename: Eric T
authors.initials: ET
authors.lastname: Larson
authors.forename: Cassie M
authors.initials: CM
authors.lastname: Bryan
authors.forename: Anna M W
authors.initials: AM
authors.lastname: Fox
authors.forename: Molly C
authors.initials: MC
authors.lastname: Reid
authors.forename: Steven M
authors.initials: SM
authors.lastname: Johnson
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Murphy
authors.forename: Mark
authors.initials: M
authors.lastname: Kennedy
authors.forename: Henning
authors.initials: H
authors.lastname: Mann
authors.forename: David J
authors.initials: DJ
authors.lastname: Leibly
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Hewitt
authors.forename: Christophe L M J
authors.initials: CL
authors.lastname: Verlinde
authors.forename: Stefan
authors.initials: S
authors.lastname: Kappe
authors.forename: Ethan A
authors.initials: EA
authors.lastname: Merritt
authors.forename: Dustin J
authors.initials: DJ
authors.lastname: Maly
authors.forename: Oliver
authors.initials: O
authors.lastname: Billker
authors.forename: Wesley C
authors.initials: WC
authors.lastname: Van Voorhis
mesh_terms: D000818:Animals; D000852:Anopheles / Q000469:parasitology*; D003140:Communicable Disease Control / Q000379:methods; D051418:Focal Adhesion Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D016778:Malaria, Falciparum / Q000201:enzymology / Q000517:prevention & control / Q000635:transmission; D051379:Mice; D010962:Plasmodium berghei / Q000201:enzymology*; D010963:Plasmodium falciparum / Q000201:enzymology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors*
chemical_list: D047428:Protein Kinase Inhibitors; D015800:Protozoan Proteins; D051418:Focal Adhesion Kinase 2