Review

Novel inhibitors of the renal inward rectifier potassium channel of the mosquito vector Aedes aegypti

Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA

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Corey R Hopkins

*Author for correspondence: Tel.: +1 402 559 9729;

E-mail Address: corey.hopkins@unmc.edu

https://orcid.org/0000-0003-4958-1697

Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA

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Published Online:30 Sep 2021https://doi.org/10.4155/fmc-2021-0189

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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.

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Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

1. Shaw WR, Catteruccia F. Vector biology meets disease control: using basic research to fight vector-borne disesaes. Nat. Microbiol. 4, 20–34 (2019).
Medline CASGoogle Scholar
2. Gates B. The deadliest animal in the world (2014). www.gatesnotes.com/health/most-lethal-animal-mosquito-week
Google Scholar
3. Ciota AT, Bialosuknia SM, Zink SD et al. Effects of Zika virus strain and Aedes mosquito species on vector competence. Emerg. Infect. Dis. 23, 1110–1117 (2017).
Medline CASGoogle Scholar
4. Fauci AS, Morens DM. Zika virus in the Americas – yet another arbovirus threat. N. Engl. J. Med. 374, 601–604 (2016).
MedlineGoogle Scholar
5. Bhatt S, Gething PW, Brady OJ et al. The global distribution and burden of dengue. Nature 496, 504–507 (2013).
Medline CASGoogle Scholar
6. WHO. Global Strategy for Dengue Prevention and Control. World Health Organization, Geneva, Switzerland, 43 (2012).
Google Scholar
7. Shepard DS, Coudeville L, Halasa YA, Zambrano B, Dayan GH. Economic impact of Dengue illness in the Americas. Am. J. Trop. Med. Hyg. 84, 200–207 (2011).
MedlineGoogle Scholar
8. Shepard DS, Undurraga EA, Halasa YA. Economic and disease burden of Dengue in southeast Asia. PLoS Negl. Trop. Dis. 7, e2055 (2013).
MedlineGoogle Scholar
9. Morrison TE. Reemergence of Chikungunya virus. J. Virol. 88, 11644–11647 (2014).
MedlineGoogle Scholar
10. Weaver SC. Arrival of Chikungunya virus in the new world: prospects for spread and impact on public health. PLoS Negl. Trop. Dis. 8, e2921 (2014).
MedlineGoogle Scholar
11. Vontas J, Kioulos E, Pavlidi N, Morou E, della Torre A, Ranson H. Insecticide resistance in the major Dengue vectors Aedes albopictus and Aedes aegypti. Pest. Biochem. Physiol. 104, 126–131 (2012).
CASGoogle Scholar
12. Ranson H, Burhani J, Lumjuan N, Black WC IV. Insecticide resistance in dengue vectors. TropIKA.net 1, 1–12 (2010).
Google Scholar
13. Goulson D, Nicholls E, Botías C, Rotheray EL. Bee declines driven by combined stress from parasites, pesticides, and lack of flowers. Science 347, 1255957 (2015).
MedlineGoogle Scholar
14. Douglas MR, Sponsler DB, Lonsdorf EV, Grozinger CM. County-level analysis reveals a rapidly shifting landscape of insecticide hazard to honey bees (Apis mellifera) on US farmland. Sci. Rep. 10, 797 (2020).
Medline CASGoogle Scholar
15. Chmiel JA, Daisley BA, Pitek AP, Thompson GJ, Reid G. 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).
Google Scholar
16. Pokhrel V, DeLisi NA, Danka RG, Walker TW, Ottea JA, Healy KB. Effects of truck-mounted, ultra low volume mosquito adulticides on honey bees (Apis mellifera) in a suburban field setting. PLoS ONE 13, e0193535 (2018).
MedlineGoogle Scholar
17. Bartlett LJ, Carlson CJ, Boots M. Identifying regions of risk to honey bees from Zika vector control in the USA. J. Apic. Res. 57, 709–719 (2018).
Google Scholar
18. Woodcock BA, Bullock JM, Shore RF et al. Country-specific effects on neonicotinoid pesticides on honey bees and wild bees. Science 356, 1391–1395 (2017).
Google Scholar
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
Google Scholar
20. Beyenbach KW, Yu Y, Piermarini PM, Denton JS. 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.
MedlineGoogle Scholar
21. Yang Z, Statler B-M, Calkins TL et al. 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).
Medline CASGoogle Scholar
22. Swale DR, Li Z, Guerrero F, Pérez De Léon AA, Foil LD. 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).
Medline CASGoogle Scholar
23. Li Z, Macaluso KR, Foil LD, Swale DR. 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).
Medline CASGoogle Scholar
24. Ren M, Niu J, Hu B et al. Block of Kir channels by fonicamid disrupts salivary and renal excretion of insect pests. Insect Biochem. Mol. Biol. 99, 17–26 (2018).
Medline CASGoogle Scholar
25. Raphemot R, Rouhier MF, Hopkins CR et al. 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.
Medline CASGoogle Scholar
26. Beyenbach KW, Piermarini PM. 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).
Medline CASGoogle Scholar
27. Rouhier MF, Hine RM, Park ST et al. 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).
Medline CASGoogle Scholar
28. Raphemot R, Weaver CD, Denton JS. High-throughput screening for small-molecule modulators of inward rectifier potassium channels. J. Vis. Exp. 71, e4209 (2013).
MedlineGoogle Scholar
29. Raphemot R, Lonergan DF, Nguyen TT et al. 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).
Medline CASGoogle Scholar
30. Ramsay JA. Active transport of water by the Malpighian tubules of the stick insect, Dixippus morosus (Orthoptera, phasmidae). J. Exp. Biol. 31, 104–113 (1954).
CASGoogle Scholar
31. Drake LL, Boudko DY, Marinotti O, Carpenter VK, Dawe AL, Hansen IA. The aquaporin gene family of the yellow fever mosquito, Aedes aegypti. PLoS ONE 5, e15578 (2010).
Medline CASGoogle Scholar
32. Williams JC, Jagedorn HH, Beyenbach KW. 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).
CASGoogle Scholar
33. Rouhier MF, Raphemot R, Denton JS, Piermarini PM. 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).
MedlineGoogle Scholar
34. Maharaj R. Global trends in insecticide resistance and impact on disease vector control measures. Open Access Insect Physiol. 3, 27 (2011).
Google Scholar
35. Raphemot R, Rouhier MF, Swale DR et al. Discovery and characterization of a potent and selective inhibitor of Aedes aegypti inward rectifier potassium channels. PLoS ONE 9, e110772 (.2014).
MedlineGoogle Scholar
36. Hibino H, Inanobe A, Furutani K, Murakami S, Findlay I, Kurachi Y. Inwardly rectifying potassium channels: their structure, function, and physiological roles. Physiol. Rev. 90, 291–366 (2010).
Medline CASGoogle Scholar
37. Willoughby L, Batterham P, Daborn PJ. Piperonyl butoxide induces the expression of cytochrome P450 and glutathione S-transferase genes in Drosophila melanogaster. Pest Manag. Sci. 63, 803–808 (2007).
Medline CASGoogle Scholar
38. Swale DR, Engers DW, Bollinger SR et al. 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.
Medline CASGoogle Scholar
39. Webb JE, Green RA. On the penetration of insecticides through the insect cuticle. J. Exp. Biol. 22, 8–20 (1945).
Medline CASGoogle Scholar
40. Aretz CD, Morwitzer MJ, Sanford AG et al. 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.
Medline CASGoogle Scholar
41. Raphemot R, Kadakia RJ, Olsen ML et al. 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).
Medline CASGoogle Scholar
42. Aretz CD, Kharade SV, Chronister K et al. Further SAR on the (phenylsulfonyl)piperazine scaffold as inhibitors of the Aedes aegypti Kir (AeKir) channel and larvicides. ChemMedChem 16, 319–327 (2021).
Medline CASGoogle Scholar
43. Waltz E. First genetically modified mosquitoes released in the United States (2021). www.nature.com/articles/d41586-021-01186-6
Google Scholar
44. Wilke ABB, Marrelli MT. Paratransgenesis: a promising new strategy for mosquito vector control. Parasit. Vectors 8, 342 (2015).
MedlineGoogle Scholar

Vol. 13, No. 22

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History

Received 28 June 2021

Accepted 9 August 2021

Published online 30 September 2021

Published in print November 2021

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Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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