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Towards Mosquitocides for Prevention of Vector-Borne Infectious Diseases: discovery and Development of Acetylcholinesterase 1 Inhibitors
Umeå University, Faculty of Science and Technology, Department of Chemistry.
2016 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
Mot nya insekticider för bekämpning av sjukdomsbärande myggor : identifiering och utveckling av acetylkolinesteras 1 inhibitorer (Swedish)
Abstract [en]

Diseases such as malaria and dengue impose great economic burdens and are a serious threat to public health, with young children being among the worst affected. These diseases are transmitted by mosquitoes, also called disease vectors, which are able to transmit both parasitic and viral infections. One of the most important strategies in the battle against mosquito-borne diseases is vector control by insecticides and the goal is to prevent people from being bitten by mosquitoes. Today’s vector control methods are seriously threatened by the development and spread of insecticide-resistant mosquitos warranting the search for new insecticides. This thesis has investigated the possibilities of vector control using non-covalent inhibitors targeting acetylcholinesterase (AChE); an essential enzyme present in mosquitoes as well as in humans and other mammals. A key requirement for such compounds to be considered safe and suitable for development into new public health insecticides is selectivity towards the mosquito enzyme AChE1. The work presented here is focused on AChE1 from the disease transmitting mosquitoes Anopheles gambiae (AgAChE1) and Aedes aegypti (AaAChE1), and their human (hAChE) and mouse (mAChE) counterparts. By taking a medicinal chemistry approach and utilizing high throughput screening (HTS), new chemical starting points have been identified. Analysis of the combined results of three different HTS campaigns targeting AgAChE1, AaAChE1, and hAChE allowed the identification of several mosquito-selective inhibitors and a number of compound classes were selected for further development. These compounds are non-covalent inhibitors of AChE1 and thereby work via a different mechanism compared to current anti-cholinergic insecticides, whose activity is the result of a covalent modification of the enzyme. The potency and selectivity of two compound classes have been explored in depth using a combination of different tools including design, organic synthesis, biochemical assays, protein X-ray crystallography and homology modeling. Several potent inhibitors with promising selectivity for the mosquito enzymes have been identified and the insecticidal activity of one new compound has been confirmed by in vivo experiments on mosquitoes. The results presented here contribute to the field of public health insecticide discovery by demonstrating the potential of selectively targeting mosquito AChE1 using non-covalent inhibitors. Further, the presented compounds can be used as tools to study mechanisms important in insecticide development, such as exoskeleton penetration and other ADME processes in mosquitoes.

Place, publisher, year, edition, pages
Umeå: Umeå universitet , 2016. , 123+27 p.
Keyword [en]
Mosquito, vector-borne diseases, vector control, insecticide, acetylcholinesterase, medicinal chemistry, high-throughput screening, organic synthesis, homology modeling, structure activity relationship, structure selectivity relationship
National Category
Organic Chemistry
Research subject
läkemedelskemi; Organic Chemistry
Identifiers
URN: urn:nbn:se:umu:diva-119924ISBN: 978-91-7601-492-9 (print)OAI: oai:DiVA.org:umu-119924DiVA: diva2:925625
Public defence
2016-05-27, KB3B1, KBC-huset, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2016-05-04 Created: 2016-05-02 Last updated: 2016-05-26Bibliographically approved
List of papers
1. Acetylcholinesterases from the Disease Vectors Aedes aegypti and Anopheles gambiae: Functional Characterization and Comparisons with Vertebrate Orthologues
Open this publication in new window or tab >>Acetylcholinesterases from the Disease Vectors Aedes aegypti and Anopheles gambiae: Functional Characterization and Comparisons with Vertebrate Orthologues
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2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 10, e0138598Article in journal (Refereed) Published
Abstract [en]

Mosquitoes of the Anopheles (An.) and Aedes (Ae.) genus are principal vectors of human diseases including malaria, dengue and yellow fever. Insecticide-based vector control is an established and important way of preventing transmission of such infections. Currently used insecticides can efficiently control mosquito populations, but there are growing concerns about emerging resistance, off-target toxicity and their ability to alter ecosystems. A potential target for the development of insecticides with reduced off-target toxicity is the cholinergic enzyme acetylcholinesterase (AChE). Herein, we report cloning, baculoviral expression and functional characterization of the wild-type AChE genes (ace-1) from An. gambiae and Ae. aegypti, including a naturally occurring insecticide-resistant (G119S) mutant of An. gambiae. Using enzymatic digestion and liquid chromatography-tandem mass spectrometry we found that the secreted proteins were post-translationally modified. The Michaelis-Menten constants and turnover numbers of the mosquito enzymes were lower than those of the orthologous AChEs from Mus musculus and Homo sapiens. We also found that the G119S substitution reduced the turnover rate of substrates and the potency of selected covalent inhibitors. Furthermore, non-covalent inhibitors were less sensitive to the G119S substitution and differentiate the mosquito enzymes from corresponding vertebrate enzymes. Our findings indicate that it may be possible to develop selective non-covalent inhibitors that effectively target both the wild-type and insecticide resistant mutants of mosquito AChE.

National Category
Other Chemistry Topics
Identifiers
urn:nbn:se:umu:diva-110996 (URN)10.1371/journal.pone.0138598 (DOI)000362511000010 ()26447952 (PubMedID)
Funder
Swedish Research Council
Available from: 2015-11-17 Created: 2015-11-02 Last updated: 2017-12-01Bibliographically approved
2. Discovery of selective inhibitors targeting acetylcholinesterase 1 from disease-transmitting mosquitoes
Open this publication in new window or tab >>Discovery of selective inhibitors targeting acetylcholinesterase 1 from disease-transmitting mosquitoes
2016 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 59, no 20, 9409-9421 p.Article in journal (Other academic) Published
Abstract [en]

Vector control of disease-transmitting mosquitoes is increasingly important due to the re-emergence and spread of infections such as malaria and dengue. We have conducted a high throughput screen (HTS) of 17,500 compounds for inhibition of the essential AChE1 enzymes from the mosquitoes Anopheles gambiae and Aedes aegypti. In a differential HTS analysis including the human AChE, several structurally diverse, potent, and selective noncovalent AChE1 inhibitors were discovered. For example, a phenoxyacetamide-based inhibitor was identified with a 100-fold selectivity for the mosquito over the human enzyme. The compound also inhibited a resistance conferring mutant of AChE1. Structure-selectivity relationships could be proposed based on the enzymes' 3D structures; the hits' selectivity profiles appear to be linked to differences in two loops that affect the structure of the entire active site. Noncovalent inhibitors of AChE1, such as the ones presented here, provide valuable starting points toward insecticides and are complementary to existing and new covalent inhibitors.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2016
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-119925 (URN)10.1021/acs.jmedchem.6b00967 (DOI)000386641300010 ()
Note

First published in thesis in manuscript form.

Available from: 2016-05-03 Created: 2016-05-02 Last updated: 2017-11-30Bibliographically approved
3. Structure-Activity and Structure-Selectivity Relationships of Thiourea-Based Inhibitors of Acetylcholinesterase 1
Open this publication in new window or tab >>Structure-Activity and Structure-Selectivity Relationships of Thiourea-Based Inhibitors of Acetylcholinesterase 1
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(English)Manuscript (preprint) (Other academic)
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-119926 (URN)
Available from: 2016-05-03 Created: 2016-05-02 Last updated: 2016-05-03

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