Insect Acetylcholinesterase as a Target for Effective and Environmentally Safe Insecticides

Pang, Yuan Ping

doi:10.1016/b978-0-12-417010-0.00006-9

Cited by 33 publications

(24 citation statements)

References 180 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…It has therefore been demonstrated that rapid and selective inhibition of Ag AChE over h AChE can be achieved with the appropriate sulfhydryl reagent. However, to date no studies of the insecticidal activity of Cys-targeting AChE inhibitors have been published [36]. Thus, despite the extremely promising in vitro results achieved, the practicality of this approach for vector control remains to be demonstrated.…”

Section: Development Of Covalent Inhibitors Of An Gambiae Ache Thmentioning

confidence: 99%

Discovery of Species-selective and Resistance-breaking Anticholinesterase Insecticides for the Malaria Mosquito

Carlier

Bloomquist

Totrov

et al. 2017

CMC

View full text Add to dashboard Cite

Great reductions in malaria mortality have been accomplished in the last 15 years, in part due to the widespread roll-out of insecticide-treated bednets across sub-Saharan Africa. To date, these nets only employ pyrethroids, insecticides that target the voltage-gated sodium ion channel of the malaria vector, Anopheles gambiae. Due to the growing emergence of An. gambiae strains that are resistant to pyrethroids, there is an urgent need to develop new public health insecticides that engage a different target and possess low mammalian toxicity. In this review, we will describe efforts to develop highly species-specific and resistance-breaking inhibitors of An. gambiae acetylcholinesterase (AgAChE). These efforts have been greatly aided by advances in knowledge of the structure of the enzyme, and two major inhibitor design strategies have been explored. Since AgAChE possesses an unpaired Cys residue not present in mammalian AChE, a logical strategy to achieve selective inhibition involves design of compounds that could ligate that Cys. A second strategy involves the design of new molecules to target the catalytic serine of the enzyme. Here the challenge is not only to achieve high inhibition selectivity vs human AChE, but also to demonstrate toxicity to An. gambiae that carry the G119S resistance mutation of AgAChE. The advances made and challenges remaining will be presented. This review is part of the special issue “Insecticide Mode of Action: From Insect to Mammalian Toxicity.

show abstract

Section: Development Of Covalent Inhibitors Of An Gambiae Ache Thmentioning

confidence: 99%

Discovery of Species-selective and Resistance-breaking Anticholinesterase Insecticides for the Malaria Mosquito

Carlier

Bloomquist

Totrov

et al. 2017

CMC

View full text Add to dashboard Cite

show abstract

“…On the other hand, Musca domestica, which belongs to the true y species, has only one type of AChE, AO-AChE, in particular. 6 The compounds chosen for selectivity screening can be divided into two groups based on their structural features. All these structures have been recently reported as potential candidates for the treatment for AD or myasthenia gravis.…”

Section: Biological Assaymentioning

confidence: 99%

“…5 All the problems caused by crop-destroying, disease-carrying, and residential insects require urgent solutions. 6 Carbamates (CA) and organophosphates (OP) are examples of pesticides that inhibit cholinesterases, which are commonly used for insect control. [7][8][9] Acetylcholinesterase (AChE; EC 3.1.1.7) is a serine esterase in the a/b hydrolase-fold enzyme family.…”

Section: Introductionmentioning

confidence: 99%

Bis-isoquinolinium and bis-pyridinium acetylcholinesterase inhibitors: in vitro screening of probes for novel selective insecticides

et al. 2017

View full text Add to dashboard Cite

Insects have a huge impact on quality of life around the world. They play roles in transmitting diseases, cropdestruction, and as residential pests. Their increased resistance to the existing pesticides and the toxicity of carbamates (CA) and organophosphates (OP) has led to the development of new environmentally safe insecticides. In our study, thirty different bis-isoquinolinium and bis-pyridinium acetylcholinesterase inhibitors were tested as candidates for potential new selective pesticides. Our compounds were evaluated in vitro on insect acetylcholinesterase (AChE) from Musca domestica and human erythrocyte AChE using the modified Ellman's method. The values of IC 50 were compared and expressed via a selectivity index (SI) towards the insect enzyme. K299, K416, and K423 provided a high SI and seem to be suitable as new lead structures of novel selective anticholinesterase insecticides. Docking studies further provided the rational background uncovering the disparities in the ligand-enzyme binding modes for each AChE enzyme. In vitro assessments as well as docking studies highlighted K299 and K416 as suitable candidates for lead structures of novel pesticides. However, further evaluation is needed to confirm this statement. View Article Online a The IC 50 values are derived from triplicate and selectivity indexes (SI) were calculated as a ratio of IC 50 value for hAChE/IC 50 value for MdAChE. b Data were obtained from ref. 30. c Data were obtained from ref. 31. 39282 | RSC Adv., 2017, 7, 39279-39291 This journal is

show abstract

“…http://dx.doi.org/10.1101/144204 doi: bioRxiv preprint first posted online May. 31, 2017; However, a cursory literature search showed a wide range of experimentally determined K i s for 9-amino-1,2,3,4-tetrahydroacridinium monohydrochloride (tacrine, a withdrawn Alzheimer's drug [6]) against acetylcholinesterase (AChE) [7][8][9][10][11][12][13] from the same species using the same spectrophotometric Ellman assay [14] under the same assay conditions (temperature, pH, and ionic strength). For example, the K i of tacrine was reported to be 20.2 ± 0.1 nM by one group and yet 340 ± 97 nM by another group for inhibiting Electrophorus electricus AChE (eeAChE) under the same Ellman assay conditions [15,16].…”

Section: Cc-by 40 International License Peer-reviewed) Is the Authormentioning

confidence: 99%

On the use of the experimentally determined enzyme inhibition constant as a measure of absolute binding affinity

Darras

Pang

2017

Preprint

Self Cite

View full text Add to dashboard Cite

Defined as a state function representing an inhibitor's absolute affinity for its target enzyme, the experimentally determined enzyme inhibition constant (K i ) is widely used to rank order binding affinities of different inhibitors for a common enzyme or different enzymes for a common inhibitor and to benchmark computational approaches to predicting binding affinity. Herein, we report that adsorption of bis (7)-tacrine to the glass container surface increased its K i against Electrophorus electricus acetylcholinesterase (eeAChE) to 3.2 ± 0.1 nM (n = 5) compared to 2.9 ± 0.4 pM (n = 5) that was determined using plastic containers with other assay conditions kept the same. We also report that, due to binding or "adsorption" of bis (7)-tacrine to the inactive eeAChE, the bis(7)-tacrine K i increased from 2.9 ± 0.4 pM (n = 5) to 734 ± 70 pM (n = 5) as the specific eeAChE activity decreased from 342 U/mg to 26 U/mg while other assay conditions were kept the same. These results caution against using K i s to rank order binding potencies, define selectivity, or benchmark computational methods without knowing detailed assay conditions.

show abstract

Insect Acetylcholinesterase as a Target for Effective and Environmentally Safe Insecticides

Cited by 33 publications

References 180 publications

Discovery of Species-selective and Resistance-breaking Anticholinesterase Insecticides for the Malaria Mosquito

Discovery of Species-selective and Resistance-breaking Anticholinesterase Insecticides for the Malaria Mosquito

Bis-isoquinolinium and bis-pyridinium acetylcholinesterase inhibitors: in vitro screening of probes for novel selective insecticides

On the use of the experimentally determined enzyme inhibition constant as a measure of absolute binding affinity

Contact Info

Product

Resources

About