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 3rd instars showing greater resistance. Mortality was also high within 24 h of exposure of 1st, 2nd and 3rd instars of An. gambiae to fosinopril. Fosinopril was also toxic to Ae. aegypti larvae, although the 1st 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.
Highlights
Inhibitors of human ACE as anti-hypertensive drugs[10,11,12]
Insect ACE resembles the mammalian enzyme in its substrate specificity, and in susceptibility to inhibitors such as captopril, lisinopril, fosinoprilat, enalapril and trandolaprilat, but apart from captopril these inhibitors can be far less potent towards insect ACE compared to mammalian ACE22,23
By measuring the peptidase activity before and after centrifugation, it was clear that the majority of the insect ACE remained in the high-speed supernatant and that most of the peptidase activity was inhibited by captopril (Fig. 2)
Summary
Inhibition of the soluble peptidyl dipeptidase (insect ACE) activity from whole larvae of Ae. aegypti and An. gambiae. Less than observed in the S2′sub-site, they could still result in significant charge changes at the binding site that will in turn influence inhibitor binding This level of detail makes AnoACE an attractive target for applying structure-based drug design to developing potent and, importantly, highly selective inhibitors which could be used as insecticides. These compounds would need to be presented to the larvae of Ae. aegypti and An. gambiae in a particulate form to maximise oral activity in these filter feeders
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