An insecticide resistance-breaking mosquitocide targeting inward rectifier potassium channels in vectors of Zika virus and malaria

Abstract

Insecticide resistance is a growing threat to mosquito control programs around the world, thus creating the need to discover novel target sites and target-specific compounds for insecticide development. Emerging evidence suggests that mosquito inward rectifier potassium (Kir) channels represent viable molecular targets for developing insecticides with new mechanisms of action. Here we describe the discovery and characterization of VU041, a submicromolar-affinity inhibitor of Anopheles (An.) gambiae and Aedes (Ae.) aegypti Kir1 channels that incapacitates adult female mosquitoes from representative insecticide-susceptible and -resistant strains of An. gambiae (G3 and Akron, respectively) and Ae. aegypti (Liverpool and Puerto Rico, respectively) following topical application. VU041 is selective for mosquito Kir channels over several mammalian orthologs, with the exception of Kir2.1, and is not lethal to honey bees. Medicinal chemistry was used to develop an analog, termed VU730, which retains activity toward mosquito Kir1 but is not active against Kir2.1 or other mammalian Kir channels. Thus, VU041 and VU730 are promising chemical scaffolds for developing new classes of insecticides to combat insecticide-resistant mosquitoes and the transmission of mosquito-borne diseases, such as Zika virus, without harmful effects on humans and beneficial insects.

Malpighian Tubules as Novel Targets for Mosquito Control

“…We have confirmed that topical application of VU041 inhibits the diuretic capacity of Ae. aegypti , consistent with an effect on the Malpighian tubules [23] (Figure 7A). Furthermore, in An.…”

“…gambiae within 24 h of topical application to the cuticle [23]. Moreover, VU041 exhibits similar efficacy against insecticide-susceptible and -resistant strains of both mosquito species [23]. We have confirmed that topical application of VU041 inhibits the diuretic capacity of Ae.…”

Chemical inhibition of Kir channels reduces salivary secretions and phloem feeding of the cotton aphid, Aphis gossypii (Glover)

“…To this point, we observed high mortality at 48‐ and 72‐h time points after foliar applications of VU041 to living cotton plants, but no acute mortality was observed after ingestion or contact exposure to VU041. Previous reports have shown Kir channels are critical for proper function of the nervous system and osmoregulatory capacities of diptera, thus mortality in these species after exposure to Kir inhibitors is likely due to altered neurological function, an inability to osmoregulate, or a combination of both. However, the lack of acute toxicity or signs of intoxication in A. gossypii after ingesting VU041 or after contact exposure, combined with the lack of phloem feeding, suggests the delayed mortality for this species is likely resultant of nutrient deficiencies stemming from the lack of phloem feeding (Fig.…”

“…The realization that Kir channels constitute a critical conductance pathway in multiple arthropod systems has driven the discovery of multiple structurally diverse and specific inhibitors of insect Kir channels . The growing pharmacological library targeting insect Kir channels has allowed for toxicological characterizations of insect Kir channels and data suggest these ion channels represent promising molecular targets for inducing acute lethality through the development of small‐molecule inhibitors . Importantly, the mosquito‐selective Kir channel inhibitor VU041 was shown to possess moderate inhibition potency to aphid Kir1 and Kir2 channels, which enabled interrogation of the physiological role and toxicological potential of aphid Kir channels.…”

“…A phylogenetic analysis of A. glycines Kir channels shows significant differences between Kir2 encoding genes of aphids when compared to other hemipteran and dipteran insects, indicating that the development of molecules with high insect species selectivity is possible. Importantly, both Kir1 and Kir2 genes in A. glycines are evolutionarily divergent to the human Kir channel family that would enable the development of highly selective molecules against human Kir channels, as was done for VU041 and related analogs . Considering the potential for development of selective insecticides and VU041‐inhibited aphid phloem feeding, investments in understanding the fundamental physiology of aphid salivary gland function and insecticide development campaigns targeting potassium channels in the salivary gland are likely to be well placed.…”