Abstract
The mosquito continues to be the most lethal animal to humans due to the devastating diseases that it carries and transmits. Controlling mosquito-borne diseases relies heavily on vector management using neurotoxic insecticides with limited modes of action. This has led to the emergence of resistance to pyrethroids and other neurotoxic insecticides in mosquitoes, which has reduced the efficacy of chemical control agents. Moreover, many neurotoxic insecticides are not selective for mosquitoes and negatively impact beneficial insects such as honeybees. Developing new mosquitocides with novel mechanisms of action is a clear unmet medical need; this review covers the efforts made toward this end by targeting the renal inward rectifier potassium channel (Kir) of the mosquito.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1. . Vector biology meets disease control: using basic research to fight vector-borne disesaes. Nat. Microbiol. 4, 20–34 (2019).
- 2. . The deadliest animal in the world (2014). www.gatesnotes.com/health/most-lethal-animal-mosquito-week
- 3. Effects of Zika virus strain and Aedes mosquito species on vector competence. Emerg. Infect. Dis. 23, 1110–1117 (2017).
- 4. . Zika virus in the Americas – yet another arbovirus threat. N. Engl. J. Med. 374, 601–604 (2016).
- 5. The global distribution and burden of dengue. Nature 496, 504–507 (2013).
- 6. WHO. Global Strategy for Dengue Prevention and Control. World Health Organization, Geneva, Switzerland, 43 (2012).
- 7. . Economic impact of Dengue illness in the Americas. Am. J. Trop. Med. Hyg. 84, 200–207 (2011).
- 8. . Economic and disease burden of Dengue in southeast Asia. PLoS Negl. Trop. Dis. 7, e2055 (2013).
- 9. . Reemergence of Chikungunya virus. J. Virol. 88, 11644–11647 (2014).
- 10. . Arrival of Chikungunya virus in the new world: prospects for spread and impact on public health. PLoS Negl. Trop. Dis. 8, e2921 (2014).
- 11. . Insecticide resistance in the major Dengue vectors Aedes albopictus and Aedes aegypti. Pest. Biochem. Physiol. 104, 126–131 (2012).
- 12. . Insecticide resistance in dengue vectors. TropIKA.net 1, 1–12 (2010).
- 13. . Bee declines driven by combined stress from parasites, pesticides, and lack of flowers. Science 347, 1255957 (2015).
- 14. . County-level analysis reveals a rapidly shifting landscape of insecticide hazard to honey bees (Apis mellifera) on US farmland. Sci. Rep. 10, 797 (2020).
- 15. . Understanding the effects of sublethal pesticide exposure on honey bees: a role for probiotics as mediators of environmental stress. Front. Ecol. Evol. 8, 22 (2020).
- 16. . Effects of truck-mounted, ultra low volume mosquito adulticides on honey bees (Apis mellifera) in a suburban field setting. PLoS ONE 13, e0193535 (2018).
- 17. . Identifying regions of risk to honey bees from Zika vector control in the USA. J. Apic. Res. 57, 709–719 (2018).
- 18. Country-specific effects on neonicotinoid pesticides on honey bees and wild bees. Science 356, 1391–1395 (2017).
- 19. BASF. BASF introduces first new class of public health insecticide for malaria prevention in more than 30 years (2017). www.basf.com/global/en/media/news-releases/2017/07/p-17-266.html
- 20. . Targeting renal epithelial channels for the control of insect vectors. Tissue Barriers 3, e1081861 (2015). • Review first suggesting the use of ion channel inhibitors as vector control agents.
- 21. Dynamic expression of genes encoding subunits of inward rectifier potassium (Kir) channels in the yellow fever mosquito Aedes aegypti. Comp. Biochem. Physiol. B 204, 35–44 (2017).
- 22. . Role of inward rectifier potassium channels in salivary gland function and sugar feeding of the fruit fly, Drosophilia melanogaster. Pestic. Biochem. Physiol. 141, 41–49 (2017).
- 23. . Inward rectifier potassium (Kir) channels mediate salivary gland function and blood feeding in the lone star tick, Amblyomma americanum. PLoS Negl. Trop. Dis. 13, e0007153 (2019).
- 24. Block of Kir channels by fonicamid disrupts salivary and renal excretion of insect pests. Insect Biochem. Mol. Biol. 99, 17–26 (2018).
- 25. Eliciting renal failure in mosquitoes with a small-molecule inhibitor of inward-rectifying potassium channels. PLoS ONE 8, e64905 (2013). • First report of a small molecule AeKir inhibitor. This report was instrumental in showing the potential of these compounds as next generation mosquitocides.
- 26. . Transcellular and paracellular pathways of transepithelial fluid secretion in Malpighian (renal) tubules of the yellow fever mosquito Aedes aegypti. Acta Physiol. (Oxf.) 202, 387–407 (2011).
- 27. The excretion of NaCl and KCl loads in mosquitoes: 2. Effects of the small molecule Kir channel modulator VU573 and its inactive analog VU342. Am. J. Physiol. Regul. Integr. Comp. Physiol. 307, R850–R861 (2014).
- 28. . High-throughput screening for small-molecule modulators of inward rectifier potassium channels. J. Vis. Exp. 71, e4209 (2013).
- 29. Discovery, characterization, and structure–activity relationships of an inhibitor of inward rectifier potassium (Kir) channels with preference for Kir2.3, Kir3.x, and Kir7.1. Front. Pharmacol. 2, 75 (2011).
- 30. . Active transport of water by the Malpighian tubules of the stick insect, Dixippus morosus (Orthoptera, phasmidae). J. Exp. Biol. 31, 104–113 (1954).
- 31. . The aquaporin gene family of the yellow fever mosquito, Aedes aegypti. PLoS ONE 5, e15578 (2010).
- 32. . Dynamic changes in flow rate and composition of urine during the post blood meal diuresis in Aedes aegypti. J. Comp. Physiol. 153, 257–266 (1983).
- 33. . Pharmacological validation of an inward-rectifier potassium (Kir) channel as an insecticide target in the yellow fever mosquito Aedes aegypti. PLoS ONE 9, e100700 (2014).
- 34. . Global trends in insecticide resistance and impact on disease vector control measures. Open Access Insect Physiol. 3, 27 (2011).
- 35. Discovery and characterization of a potent and selective inhibitor of Aedes aegypti inward rectifier potassium channels. PLoS ONE 9, e110772 (.2014).
- 36. . Inwardly rectifying potassium channels: their structure, function, and physiological roles. Physiol. Rev. 90, 291–366 (2010).
- 37. . Piperonyl butoxide induces the expression of cytochrome P450 and glutathione S-transferase genes in Drosophila melanogaster. Pest Manag. Sci. 63, 803–808 (2007).
- 38. An insecticide resistance-breaking mosquitocide targeting inward rectifier potassium channels in vectors of Zika virus and malaria. Sci. Rep. 6, 36954 (2016). •• First report of a topically active AeKir inhibitor.
- 39. . On the penetration of insecticides through the insect cuticle. J. Exp. Biol. 22, 8–20 (1945).
- 40. Discovery and characterization of 2-nitro-5-(4-(phenylsulfonyl)piperazin-1-yl)-N-(pyridin-4-ylmethyl)anilines as novel inhibitors of the Aedes aegypti Kir1 (AeKir1) channel. ACS Infect. Dis. 5, 917–931 (2019). •• Discovery of a new scaffold of AeKir inhibitors that are active against both adult mosquitoes and larvae. Compounds also have activity against insecticide-resistant mosquito strains.
- 41. Development and validation of fluorescence-based and automated patch clamp-based functional assays for the inward rectifier potassium channel kir4.1. Assay Drug Dev. Technol. 11, 532–543 (2013).
- 42. Further SAR on the (phenylsulfonyl)piperazine scaffold as inhibitors of the Aedes aegypti Kir (AeKir) channel and larvicides. ChemMedChem 16, 319–327 (2021).
- 43. . First genetically modified mosquitoes released in the United States (2021). www.nature.com/articles/d41586-021-01186-6
- 44. . Paratransgenesis: a promising new strategy for mosquito vector control. Parasit. Vectors 8, 342 (2015).