The toxicity of angiotensin converting enzyme inhibitors to larvae of the disease vectors Aedes aegypti and Anopheles gambiae

• Published in: Scientific reports 2017-03, Vol.7 (1), p.45409, Article 45409
• Main Authors: Abu Hasan, Zatul-’Iffah, Williams, Helen, Ismail, Nur M., Othman, Hidayatulfathi, Cozier, Gyles E., Acharya, K. Ravi, Isaac, R. Elwyn
• Format: Article
• Language: English
• Subjects: 631/601/1466; 631/92/607/468; 692/699; 82; Aedes - drug effects; Aedes aegypti; Angiotensin-converting enzyme inhibitors; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Animals; Anopheles - drug effects; Bradykinin; Captopril - pharmacology; Dipeptidase; Disease Vectors; Diuretics; Drug development; Enzymes; Fosinopril - analogs & derivatives; Fosinopril - pharmacology; Homology; Humanities and Social Sciences; Humans; Insecticide Resistance - drug effects; Insecticides - pharmacology; Instars; Larva - drug effects; Larvicides; Mosquito Vectors - drug effects; Mosquitoes; multidisciplinary; Peptidase; Peptidyl-dipeptidase A; Peptidyl-Dipeptidase A - metabolism; Pesticide resistance; Science; Toxicity; Trypsin; Vectors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep45409

The control of mosquitoes is threatened by the appearance of insecticide resistance and therefore new control chemicals are urgently required. Here we show that inhibitors of mosquito peptidyl dipeptidase, a peptidase related to mammalian angiotensin-converting enzyme (ACE), are insecticidal to larvae of the mosquitoes, Aedes aegypti and Anopheles gambiae. ACE inhibitors (captopril, fosinopril and fosinoprilat) and two peptides (trypsin-modulating oostatic factor/TMOF and a bradykinin-potentiating peptide, BPP-12b) were all inhibitors of the larval ACE activity of both mosquitoes. Two inhibitors, captopril and fosinopril (a pro-drug ester of fosinoprilat), were tested for larvicidal activity. Within 24 h captopril had killed >90% of the early instars of both species with 3 rd instars showing greater resistance. Mortality was also high within 24 h of exposure of 1 st , 2 nd and 3 rd instars of An. gambiae to fosinopril. Fosinopril was also toxic to Ae. aegypti larvae, although the 1 st instars appeared to be less susceptible to this pro-drug even after 72 h exposure. Homology models of the larval An. gambiae ACE proteins (AnoACE2 and AnoACE3) reveal structural differences compared to human ACE, suggesting that structure-based drug design offers a fruitful approach to the development of selective inhibitors of mosquito ACE enzymes as novel larvicides.