Novel target sites to control the malaria vector, Anopheles gambiae (Ag), are needed due to the increasing prevalence of pyrethroid resistance.  Our group has explored the insecticidal potential of inwardly rectifying potassium (Kir) channels since they serve critical functions in mammalian physiology, yet are unexplored in mosquitoes.  We recently reported that inhibition of Kir channels induces renal (Malpighian tubule) failure, suggesting Kir channels represent promising targets for novel mosquitocides.  Here, we heterologously express the AgKir1 channel and conduct a high-throughput screen of 25,000 small-molecule inhibitors.  Ten mosquito-selective and moderately potent (IC50 = 0.5-10 mm) inhibitors were identified.  Topical application of these inhibitors killed adult mosquitoes (LD50: 1 mg/insect).  Furthermore, non-toxic doses of AgKir1 inhibitors significantly delayed the rate of blood meal processing by ~35%, suggesting a disruption of excretory functions.  These inhibitors represent the first topically active mosquitocides targeting Kir channels and are promising candidates for optimization with medicinal chemistry.

Development of novel mosquitocides targeting inwardly rectifying potassium channels in the malaria vector, <i>Anopheles gambiae</i>

248th National Meeting (2014)

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Development of novel mosquitocides targeting inwardly rectifying potassium channels in the malaria vector, Anopheles gambiae