On July 29, 2024, the US FDA approved Alpha Cognition Inc.’s ALPHA-1062 (Zunveyl).®), an Acetylcholinesterase (AChE) inhibitor, for the treatment of mild to moderate Alzheimer’s disease. This condition affects approximately 6.7 million people in the United States. More than 70% of physicians are dissatisfied with current therapies due to side effects and limited efficacy, with more than 50% of patients discontinuing treatment within a year. As research into AChEIs continues, the importance of ALPHA-1062 and similar molecules as therapeutic options for neurodegenerative diseases is becoming increasingly apparent.
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Mechanism of action
Acetylcholinesterase (AChE) breaks down the neurotransmitter acetylcholine into choline and acetate at synaptic junctions. This process is crucial for terminating synaptic transmission, especially at neuromuscular junctions and cholinergic synapses in the nervous system. The mechanism of action of AChE involves two critical sites: the anionic site and the esteratic site.
- Anionic site: This site initially attracts and binds acetylcholine, made possible by the positively charged quaternary amine, which interacts with the negatively charged environment of the anionic site.
- Esteratic site: After binding to the anionic site, acetylcholine is transferred to the esteratic site, where it undergoes hydrolysis. This site contains a catalytic triad consisting of serine, histidine, and glutamate amino acids. The serine acts as a nucleophile and attacks the carbonyl carbon of acetylcholine, leading to the cleavage of the ester bond between acetyl and choline. This reaction results in the formation of acetate and choline.
The rapid hydrolysis of acetylcholine by AChE is essential for the regulation of neurotransmitter levels in the synaptic cleft, ensuring that nerve impulses are accurately transmitted or stopped as necessary. By controlling the duration of acetylcholine activity, AChE plays a crucial role in muscle contraction, learning, memory and other neurobiological processes.
AChE as a drug target of Alzheimer’s disease
In the treatment of Alzheimer’s disease, ACE is targeted for its role in the rapid breakdown of acetylcholine, affecting cognitive functions such as memory and learning. Therapeutic strategies aim to increase acetylcholine concentrations, which may improve cognitive function and alleviate symptoms of Alzheimer’s disease.
As a leading supplier of reagents, Sino Biological offers recombinant AChE proteins that can be used to investigate the biological role and interactions of AChE and help evaluate the impact of potential inhibitors. AChE-specific antibodies are another crucial tool, allowing the detection and quantification of the enzyme in different tissues, which is crucial for understanding its pathological and physiological roles. In addition to AChE, Sino Biological offers other drug targets and biomarkers, such as Tau, BACE1 and ApoE, to fully support drug discovery and diagnostics development for Alzheimer’s disease.