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Acetylcholinesterase: 'classical' and 'non-classical' functions and pharmacology
Israel Silman1, Joel L Sussman
1Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel. Israel.Silman@weizmann.ac.il
Current Opinion in Pharmacology
|May 24, 2005
Summary
Acetylcholinesterase (AChE) terminates nerve signals and is a target for drugs. Novel drugs target AChE's peripheral site, not its active site, for new therapeutic strategies.
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Acetylcholinesterase (AChE) is a crucial synaptic enzyme terminating cholinergic neurotransmission.
- AChE anchors in the synaptic cleft via a specialized device involving catalytic subunit tetramers and a polyproline II helix.
- AChE is a known target for nerve agents, insecticides, and anti-Alzheimer's drugs.
Purpose of the Study:
- To explore the structure and function of acetylcholinesterase (AChE).
- To investigate the non-classical roles of AChE beyond synaptic transmission.
- To identify novel therapeutic targets on AChE for drug development.
Main Methods:
- Structure-based drug design.
- Target-guided synthesis of anticholinesterase agents.
- Investigating AChE's interaction with amyloid beta (Abeta) fibrils.
Main Results:
- AChE plays non-classical roles, including acting as an adhesion protein and accelerating Abeta assembly into amyloid fibrils.
- These non-classical functions involve the peripheral anionic site at the entrance of the active-site gorge.
- Potent anticholinesterase agents have been developed using target-guided and structure-based approaches.
Conclusions:
- Novel anticholinesterase drugs are being developed to target the peripheral anionic site of AChE.
- This strategy offers a new direction for therapeutic intervention, distinct from targeting the active site.
- Understanding AChE's diverse roles opens avenues for developing drugs against neurological disorders and other conditions.