title: The toxicity of angiotensin converting enzyme inhibitors to larvae of the disease vectors Aedes aegypti and Anopheles gambiae.
abstract: 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 3rdinstars showing greater resistance. Mortality was also high within 24 h of exposure of 1st, 2ndand 3rdinstars of An. gambiae to fosinopril. Fosinopril was also toxic to Ae. aegypti larvae, although the 1stinstars 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.
authors.affiliation: Faculty of Medicine and Health Sciences, Universiti Sains Islam Malaysia, 13th Floor, Menara B, Persiaran MPAJ, Jalan Pandan Utama, Pandan Indah, 55100, Kuala Lumpur, Malaysia.|School of Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Zatul-'Iffah
authors.initials: Z'
authors.lastname: Abu Hasan
authors.affiliation: Liverpool Insect Testing Establishment, Department of Vector Biology, Liverpool School of Tropical Medicine, 1 Pembroke Place, Liverpool L3 5QA, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Williams
authors.affiliation: School of Diagnostic &Applied Health Sciences, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abd Aziz, 50300, Kuala Lumpur, Malaysia.
authors.forename: Nur M
authors.initials: NM
authors.lastname: Ismail
authors.affiliation: School of Diagnostic &Applied Health Sciences, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abd Aziz, 50300, Kuala Lumpur, Malaysia.
authors.forename: Hidayatulfathi
authors.initials: H
authors.lastname: Othman
authors.affiliation: Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK.
authors.forename: Gyles E
authors.initials: GE
authors.lastname: Cozier
authors.affiliation: Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK.
authors.forename: K Ravi
authors.initials: KR
authors.lastname: Acharya
authors.affiliation: School of Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: R Elwyn
authors.initials: RE
authors.lastname: Isaac
mesh_terms: D000330:Aedes / Q000187:drug effects*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000852:Anopheles / Q000187:drug effects*; D002216:Captopril / Q000494:pharmacology; D004199:Disease Vectors; D017328:Fosinopril / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D007305:Insecticide Resistance / Q000187:drug effects; D007306:Insecticides / Q000494:pharmacology; D007814:Larva / Q000187:drug effects*; D000072138:Mosquito Vectors / Q000187:drug effects; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D007306:Insecticides; D002216:Captopril; D007703:Peptidyl-Dipeptidase A; D017328:Fosinopril; C046965:fosinoprilat