umu.sePublications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Discovery of selective inhibitors targeting acetylcholinesterase 1 from disease-transmitting mosquitoes
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.
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. Vol. 59, no 20, 9409-9421 p.
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:umu:diva-119925DOI: 10.1021/acs.jmedchem.6b00967ISI: 000386641300010OAI: oai:DiVA.org:umu-119925DiVA: diva2:925775
Note

First published in thesis in manuscript form.

Available from: 2016-05-03 Created: 2016-05-02 Last updated: 2017-05-10Bibliographically approved
In thesis
1. Towards Mosquitocides for Prevention of Vector-Borne Infectious Diseases: discovery and Development of Acetylcholinesterase 1 Inhibitors
Open this publication in new window or tab >>Towards Mosquitocides for Prevention of Vector-Borne Infectious Diseases: discovery and Development of Acetylcholinesterase 1 Inhibitors
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Mot nya insekticider för bekämpning av sjukdomsbärande myggor : identifiering och utveckling av acetylkolinesteras 1 inhibitorer
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
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:nbn:se:umu:diva-119924 (URN)978-91-7601-492-9 (ISBN)
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
2. 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

Open Access in DiVA

No full text

Other links

Publisher's full text

Search in DiVA

By author/editor
Engdahl, CeciliaKnutsson, SofieLinusson, Anna
By organisation
Department of Chemistry
In the same journal
Journal of Medicinal Chemistry
Organic Chemistry

Search outside of DiVA

GoogleGoogle Scholar

Altmetric score

Total: 323 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf