Targeting α7 nicotinic acetylcholine receptors and their protein interactions in Alzheimer’s disease drug development
The decades-old cholinergic hypothesis of Alzheimer’s (AD) brought to clinical testing and Food and drug administration approval of acetylcholinesterase inhibitor drugs. Subsequently, the a7 nicotinic acetylcholine receptor (a7nAChR) was suggested like a new drug target for enhancing cholinergic neurotransmission. Nearly concurrently, soluble amyloid ß1-42 (Aß42 ) was proven to bind a7nAChR with picomolar affinity to activate kinases that hyperphosphorylate tau, the precursor to tau-that contains tangles. Multiple biopharmaceutical companies explored a7nAChR like a drug target for AD, mostly to boost neurotransmission. Directly targeting a7nAChR demonstrated to become a drug development challenge. The ultra-high-affinity interaction between Aß42 and a7nAChR posed a substantial hurdle for direct competition within the AD brain. The receptor quickly desensitizes, undermining effectiveness of agonists. Drug discovery approaches therefore incorporated partial agonists and allosteric modulators of a7nAChR. After substantial effort, numerous drug candidates were abandoned because of insufficient effectiveness or drug-related toxicities. As alternatives, proteins getting together with a7nAChR were searched for. In 2016, a singular nAChR regulator was identified, but no drug candidates emerged out of this effort. This Year, the interaction of filamin A with a7nAChR was proven to become important to Aß42 ‘s toxic signaling via a7nAChR, presenting a brand new drug target. The novel drug candidate simufilam disrupts the filamin A-a7nAChR interaction, reduces Aß42 ‘s high-affinity binding to a7nAChR, and suppresses Aß42 ‘s toxic signaling. Early numerous studies of simufilam demonstrated enhancements in experimental CSF biomarkers and warning signs of cognitive improvement in mild AD patients at 12 months. Simufilam is presently in phase 3 numerous studies like a disease-modifying strategy to AD.