Abstract
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.
Keywords: Acetylcholinesterase, sulfhydryl reagents, cysteine, carbamates, trifluoromethyl ketones, difluoromethyl ketones.
Current Medicinal Chemistry
Title:Discovery of Species-selective and Resistance-breaking Anticholinesterase Insecticides for the Malaria Mosquito
Volume: 24 Issue: 27
Author(s): Paul R. Carlier*, Jeffrey R. Bloomquist, Max Totrov and Jianyong Li
Affiliation:
- Department of Chemistry, Virginia Tech, Blacksburg, VA 24061,United States
Keywords: Acetylcholinesterase, sulfhydryl reagents, cysteine, carbamates, trifluoromethyl ketones, difluoromethyl ketones.
Abstract: 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.
Export Options
About this article
Cite this article as:
Carlier R. Paul*, Bloomquist R. Jeffrey, Totrov Max and Li Jianyong, Discovery of Species-selective and Resistance-breaking Anticholinesterase Insecticides for the Malaria Mosquito, Current Medicinal Chemistry 2017; 24 (27) . https://dx.doi.org/10.2174/0929867324666170206130024
DOI https://dx.doi.org/10.2174/0929867324666170206130024 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Identification of Pyrazole Derivative as an Antiviral Agent Against Chikungunya Through HTVS
Letters in Drug Design & Discovery The Role of α7 Nicotinic Acetylcholine Receptors and α7-Specific Antibodies in Neuroinflammation Related to Alzheimer Disease
Current Pharmaceutical Design Mechanism(s) Involved in Opioid Drug Abuse Modulation of HAND
Current HIV Research Podocyte Mitosis – A Catastrophe
Current Molecular Medicine Altering the Tropism of Lentiviral Vectors through Pseudotyping
Current Gene Therapy Translating Genetic Findings into Therapy in Parkinson Disease
Recent Patents on CNS Drug Discovery (Discontinued) New Insights into Chemistry and Anti-Infective Potential of Triazole Scaffold
Current Medicinal Chemistry A Scientometrics Analysis and Visualization of Depressive Disorder
Current Neuropharmacology Preliminary Anti-Coxsackie Activity of Novel 1-[4-(5,6-dimethyl(H)- 1H(2H)-benzotriazol-1(2)-yl)phenyl]-3-alkyl(aryl)ureas
Medicinal Chemistry A Critical Analysis of New Molecular Targets and Strategies for Drug Developments in Alzheimers Disease
Current Drug Targets Identification of Novel Anti-inflammatory Agents from Ayurvedic Medicine for Prevention of Chronic Diseases: “Reverse Pharmacology” and “Bedside to Bench” Approach
Current Drug Targets Oral Mucosal Immunization: Recent Advancement and Future Prospects
Current Immunology Reviews (Discontinued) EDITORIAL
Current Signal Transduction Therapy Photosensitizers Mediated Photodynamic Inactivation Against Virus Particles
Mini-Reviews in Medicinal Chemistry Therapeutic Potential of Citronella Essential Oil: A Review
Current Drug Discovery Technologies Gene Therapy in the Anterior Eye Segment
Current Gene Therapy Neuroprotective Properties of Peroxisome Proliferator-Activated Receptor Alpha (PPARα) and its Lipid Ligands
Current Medicinal Chemistry Pancreatic Islet Transplantation in Type 1 Diabetes Mellitus: An Update on Recent Developments
Current Diabetes Reviews CIITA and the MHCII Enhanceosome in the Regulation of MHCII Expression
Current Genomics GEMSP: A New Therapeutic Approach to Multiple Sclerosis
Central Nervous System Agents in Medicinal Chemistry