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Binding Mode of Reversible Inhibitors in Mosquito Acetylcholinesterase 1 Governs their Selective and Resistance-Breaking Potency
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
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(English)Manuscript (preprint) (Other academic)
National Category
Organic Chemistry
Research subject
läkemedelskemi
Identifiers
URN: urn:nbn:se:umu:diva-134619OAI: oai:DiVA.org:umu-134619DiVA: diva2:1094458
Available from: 2017-05-10 Created: 2017-05-10 Last updated: 2017-05-10
In thesis
1. Selective inhibition of acetylcholinesterase 1 from disease-transmitting mosquitoes: design and development of new insecticides for vector control
Open this publication in new window or tab >>Selective inhibition of acetylcholinesterase 1 from disease-transmitting mosquitoes: design and development of new insecticides for vector control
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Acetylcholinesterase (AChE) is an essential enzyme with an evolutionary conserved function: to terminate nerve signaling by rapid hydrolysis of the neurotransmitter acetylcholine. AChE is an important target for insecticides. Vector control by the use of insecticide-based interventions is today the main strategy for controlling mosquito-borne diseases that affect millions of people each year. However, the efficiency of many insecticides is challenged by resistant mosquito populations, lack of selectivity and off-target toxicity of currently used compounds. New selective and resistance-breaking insecticides are needed for an efficient vector control also in the future. In the work presented in this thesis, we have combined structural biology, biochemistry and medicinal chemistry to characterize mosquito AChEs and to develop selective and resistance-breaking inhibitors of this essential enzyme from two disease-transmitting mosquitoes.We have identified small but important structural and functional differences between AChE from mosquitoes and AChE from vertebrates. The significance of these differences was emphasized by a high throughput screening campaign, which made it evident that the evolutionary distant AChEs display significant differences in their molecular recognition. These findings were exploited in the design of new inhibitors. Rationally designed and developed thiourea- and phenoxyacetamide-based non-covalent inhibitors displayed high potency on both wild type and insecticide insensitive AChE from mosquitoes. The best inhibitors showed over 100-fold stronger inhibition of mosquito than human AChE, and proved insecticide potential as they killed both adult and larvae mosquitoes.We show that mosquito and human AChE have different molecular recognition and that non-covalent selective inhibition of AChE from mosquitoes is possible. We also demonstrate that inhibitors can combine selectivity with sub-micromolar potency for insecticide resistant AChE.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2017. 67 p.
Keyword
acetylcholinesterase, non-covalent inhibitor, vector control, insecticide, mosquito, vector-borne disease, high throughput screening, rational design
National Category
Biochemistry and Molecular Biology
Research subject
Biochemistry; läkemedelskemi
Identifiers
urn:nbn:se:umu:diva-134625 (URN)978-91-7601-723-4 (ISBN)
Public defence
2017-06-02, KB.E3.03 (stora hörsalen), KBC-huset, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2017-05-12 Created: 2017-05-10 Last updated: 2017-05-12Bibliographically approved

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