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- Andersson, C. David, et al.
(författare)
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Divergent Structure-Activity Relationships of Structurally Similar Acetylcholinesterase Inhibitors
- 2013
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 56:19, s. 7615-7624
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Tidskriftsartikel (refereegranskat)abstract
- The molecular interactions between the enzyme acetylcholinesterase (AChE) and two compound classes consisting of N-[2-(diethylamino)ethyl]benzenesulfonamides and N-[2-(diethylamino)ethyl]benzenemethanesulfonamides have been investigated using organic synthesis, enzymatic assays, X-ray crystallography, and thermodynamic profiling. The inhibitors' aromatic properties were varied to establish structure activity relationships (SAR) between the inhibitors and the peripheral anionic site (PAS) of AChE. The two structurally similar compound classes proved to have distinctly divergent SARs in terms of their inhibition capacity of AChE. Eight X-ray structures revealed that the two sets have different conformations in PAS. Furthermore, thermodynamic profiles of the binding between compounds and AChE revealed class-dependent differences of the entropy/enthalpy contributions to the free energy of binding. Further development of the entropy-favored compound class resulted in the synthesis of the most potent inhibitor and an extension beyond the established SARs. The divergent SARs will be utilized to develop reversible inhibitors of AChE into reactivators of nerve agent-inhibited AChE.
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| 5. |
- Edsman, Lennart, et al.
(författare)
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Detection of crayfish plague spores in large freshwater systems
- 2014
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Ingår i: Journal of Applied Ecology. - : Wiley. - 0021-8901 .- 1365-2664. ; 51, s. 544-553
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Tidskriftsartikel (refereegranskat)abstract
- Our study demonstrates a low amount of pathogen spores are present in aquatic environments with non-indigenous crayfish species, emphasizing the need for large-volume filtering techniques for successful detection. The approach can be used for risk assessments and to improve conservation and management strategies of crayfish in Europe. Applications of this method include targeted disease surveillance, habitat evaluation prior to crayfish re-stockings and water monitoring that can minimize disease transmission and spread, for example in crayfish farms and prior to fish movements for stocking purposes.
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| 6. |
- Engdahl, Cecilia, et al.
(författare)
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Acetylcholinesterases from the Disease Vectors Aedes aegypti and Anopheles gambiae : Functional Characterization and Comparisons with Vertebrate Orthologues
- 2015
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:10
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 7. |
- Engdahl, Cecilia, et al.
(författare)
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Discovery of selective inhibitors targeting acetylcholinesterase 1 from disease-transmitting mosquitoes
- 2016
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 59:20, s. 9409-9421
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 8. |
- Engdahl, Cecilia, 1987-
(författare)
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Selective inhibition of acetylcholinesterase 1 from disease-transmitting mosquitoes : design and development of new insecticides for vector control
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 9. |
- Engdahl, Fredrik, et al.
(författare)
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A Trial of Natural Habitat Enclosure Traps as a Sampling Tool for Juvenile Crayfish
- 2013
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Ingår i: Freshwater Crayfish. - 2076-4324 .- 2076-4332. ; 2, s. 137-144
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Tidskriftsartikel (refereegranskat)abstract
- Recruitment is a vital factor in the assessment, management and population dynamics of decapods. Since the juvenile stages of crayfish often prefer heterogeneous habitats, sampling with quantitative and reproducible methods have so far been challenging. We evaluate a new quantitative sampling method for juvenile crayfish; the enclosure trap. A field test was carried out during two consecutive years on a population of signal crayfish, Pacifastacus leniusculus, in littoral areas of Swedish Lake Erken. The densities of 0+ crayfish varied substantially with year, sampling date and substrate type. As expected, juvenile crayfish densities decreased over time in both study years, indicating a high mortality rate during their first year of life. Juveniles preferred gravel and stone over soft and sand substrates. Mean growth rate varied from 0.15 to 0.22 mm day-1. We evaluate this method and present recommendations for how to design and optimize field studies using enclosure traps. We conclude that enclosure traps can be used to collect valuable data on density, growth and habitat preference of juvenile crayfish, thus providing useful information for studies on population dynamics and increasing the understanding of crayfish recruitment processes.
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| 10. |
- Engdahl, Fredrik
(författare)
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Air - for Health and Comfort, An Analysis of HVAC Systems' Performance in Theory and Practice
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- One part of the objective is to analyze how different ventilation systems perform in practice when it comes to supplying and exhausting designed air flow in different outdoor and indoor conditions. The other part is to analyze the design criterias and the energy use of a variable air volume system based on controlled static pressure at the branch duct level and supplying outdoor air only. To investigate the technical status of ventilation systems, the result from the compulsory testing and examination of ventilation systems (OVK) is used. A multi-zone model (COMIS) is used to study the air flow in a multi-family building. Two ventilation systems are analyzed with the same building; the mechanical exhaust and the mechanical supply and exhaust system. Fundamental pressure loss equations, measurements and a computer program are used to determine how much the air flow at the air terminals on a branch with controlled static pressure differs. A model is developed to determine the optimal supply air temperature with respect to energy use. An average of 34% of the studied ventilation systems performed as intended. Both the mechanical exhaust and the mechanical supply and exhaust air system showed sensitiveness to outdoor temperature, building airtightness and wind. When the static pressure is controlled to be constant at the branch duct level it is possible to vary the air flow to different zones without measuring the individual flow and without significantly influence the air flow to other zones. When using 100% outdoor air the indoor air quality will be improved during most of the year. There is a great potential in controlling the supply air temperature optimally to reduce the energy use.
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