Targeting α7 nicotinic acetylcholine receptors and their protein interactions in Alzheimer's disease drug development
The decades-old cholinergic hypothesis of Alzheimer's disease (AD) led to clinical testing and FDA approval of acetylcholinesterase inhibitor drugs. Subsequently, the α7 nicotinic acetylcholine receptor (α7nAChR) was proposed as a new drug target for enhancing cholinergic neurotransmission. Nea...
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Published in | Drug development research Vol. 84; no. 6; pp. 1085 - 1095 |
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Main Authors | , , |
Format | Journal Article |
Language | English |
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01.09.2023
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Abstract | The decades-old cholinergic hypothesis of Alzheimer's disease (AD) led to clinical testing and FDA approval of acetylcholinesterase inhibitor drugs. Subsequently, the α7 nicotinic acetylcholine receptor (α7nAChR) was proposed as a new drug target for enhancing cholinergic neurotransmission. Nearly simultaneously, soluble amyloid β
(Aβ
) was shown to bind α7nAChR with picomolar affinity to activate kinases that hyperphosphorylate tau, the precursor to tau-containing tangles. Multiple biopharmaceutical companies explored α7nAChR as a drug target for AD, mostly to enhance neurotransmission. Directly targeting α7nAChR proved to be a drug development challenge. The ultra-high-affinity interaction between Aβ
and α7nAChR posed a significant hurdle for direct competition in the AD brain. The receptor rapidly desensitizes, undermining efficacy of agonists. Drug discovery approaches therefore included partial agonists and allosteric modulators of α7nAChR. After substantial effort, numerous drug candidates were abandoned due to lack of efficacy or drug-related toxicities. As alternatives, proteins interacting with α7nAChR were sought. In 2016, a novel nAChR regulator was identified, but no drug candidates have emerged from this effort. In 2012, the interaction of filamin A with α7nAChR was shown to be critical to Aβ
's toxic signaling via α7nAChR, presenting a new drug target. The novel drug candidate simufilam disrupts the filamin A-α7nAChR interaction, reduces Aβ
's high-affinity binding to α7nAChR, and suppresses Aβ
's toxic signaling. Early clinical trials of simufilam showed improvements in experimental CSF biomarkers and indications of cognitive improvement in mild AD patients at 1 year. Simufilam is currently in phase 3 clinical trials as a disease-modifying treatment for AD. |
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AbstractList | The decades‐old cholinergic hypothesis of Alzheimer's disease (AD) led to clinical testing and FDA approval of acetylcholinesterase inhibitor drugs. Subsequently, the α7 nicotinic acetylcholine receptor (α7nAChR) was proposed as a new drug target for enhancing cholinergic neurotransmission. Nearly simultaneously, soluble amyloid β1‐42 (Aβ42) was shown to bind α7nAChR with picomolar affinity to activate kinases that hyperphosphorylate tau, the precursor to tau‐containing tangles. Multiple biopharmaceutical companies explored α7nAChR as a drug target for AD, mostly to enhance neurotransmission. Directly targeting α7nAChR proved to be a drug development challenge. The ultra‐high‐affinity interaction between Aβ42 and α7nAChR posed a significant hurdle for direct competition in the AD brain. The receptor rapidly desensitizes, undermining efficacy of agonists. Drug discovery approaches therefore included partial agonists and allosteric modulators of α7nAChR. After substantial effort, numerous drug candidates were abandoned due to lack of efficacy or drug‐related toxicities. As alternatives, proteins interacting with α7nAChR were sought. In 2016, a novel nAChR regulator was identified, but no drug candidates have emerged from this effort. In 2012, the interaction of filamin A with α7nAChR was shown to be critical to Aβ42's toxic signaling via α7nAChR, presenting a new drug target. The novel drug candidate simufilam disrupts the filamin A–α7nAChR interaction, reduces Aβ42's high‐affinity binding to α7nAChR, and suppresses Aβ42's toxic signaling. Early clinical trials of simufilam showed improvements in experimental CSF biomarkers and indications of cognitive improvement in mild AD patients at 1 year. Simufilam is currently in phase 3 clinical trials as a disease‐modifying treatment for AD. The decades-old cholinergic hypothesis of Alzheimer's disease (AD) led to clinical testing and FDA approval of acetylcholinesterase inhibitor drugs. Subsequently, the α7 nicotinic acetylcholine receptor (α7nAChR) was proposed as a new drug target for enhancing cholinergic neurotransmission. Nearly simultaneously, soluble amyloid β (Aβ ) was shown to bind α7nAChR with picomolar affinity to activate kinases that hyperphosphorylate tau, the precursor to tau-containing tangles. Multiple biopharmaceutical companies explored α7nAChR as a drug target for AD, mostly to enhance neurotransmission. Directly targeting α7nAChR proved to be a drug development challenge. The ultra-high-affinity interaction between Aβ and α7nAChR posed a significant hurdle for direct competition in the AD brain. The receptor rapidly desensitizes, undermining efficacy of agonists. Drug discovery approaches therefore included partial agonists and allosteric modulators of α7nAChR. After substantial effort, numerous drug candidates were abandoned due to lack of efficacy or drug-related toxicities. As alternatives, proteins interacting with α7nAChR were sought. In 2016, a novel nAChR regulator was identified, but no drug candidates have emerged from this effort. In 2012, the interaction of filamin A with α7nAChR was shown to be critical to Aβ 's toxic signaling via α7nAChR, presenting a new drug target. The novel drug candidate simufilam disrupts the filamin A-α7nAChR interaction, reduces Aβ 's high-affinity binding to α7nAChR, and suppresses Aβ 's toxic signaling. Early clinical trials of simufilam showed improvements in experimental CSF biomarkers and indications of cognitive improvement in mild AD patients at 1 year. Simufilam is currently in phase 3 clinical trials as a disease-modifying treatment for AD. Abstract The decades‐old cholinergic hypothesis of Alzheimer's disease (AD) led to clinical testing and FDA approval of acetylcholinesterase inhibitor drugs. Subsequently, the α7 nicotinic acetylcholine receptor (α7nAChR) was proposed as a new drug target for enhancing cholinergic neurotransmission. Nearly simultaneously, soluble amyloid β 1‐42 (Aβ 42 ) was shown to bind α7nAChR with picomolar affinity to activate kinases that hyperphosphorylate tau, the precursor to tau‐containing tangles. Multiple biopharmaceutical companies explored α7nAChR as a drug target for AD, mostly to enhance neurotransmission. Directly targeting α7nAChR proved to be a drug development challenge. The ultra‐high‐affinity interaction between Aβ 42 and α7nAChR posed a significant hurdle for direct competition in the AD brain. The receptor rapidly desensitizes, undermining efficacy of agonists. Drug discovery approaches therefore included partial agonists and allosteric modulators of α7nAChR. After substantial effort, numerous drug candidates were abandoned due to lack of efficacy or drug‐related toxicities. As alternatives, proteins interacting with α7nAChR were sought. In 2016, a novel nAChR regulator was identified, but no drug candidates have emerged from this effort. In 2012, the interaction of filamin A with α7nAChR was shown to be critical to Aβ 42 's toxic signaling via α7nAChR, presenting a new drug target. The novel drug candidate simufilam disrupts the filamin A–α7nAChR interaction, reduces Aβ 42 's high‐affinity binding to α7nAChR, and suppresses Aβ 42 's toxic signaling. Early clinical trials of simufilam showed improvements in experimental CSF biomarkers and indications of cognitive improvement in mild AD patients at 1 year. Simufilam is currently in phase 3 clinical trials as a disease‐modifying treatment for AD. |
Author | Burns, Lindsay H Pei, Zhe Wang, Hoau-Yan |
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Snippet | The decades-old cholinergic hypothesis of Alzheimer's disease (AD) led to clinical testing and FDA approval of acetylcholinesterase inhibitor drugs.... Abstract The decades‐old cholinergic hypothesis of Alzheimer's disease (AD) led to clinical testing and FDA approval of acetylcholinesterase inhibitor drugs.... The decades‐old cholinergic hypothesis of Alzheimer's disease (AD) led to clinical testing and FDA approval of acetylcholinesterase inhibitor drugs.... |
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SubjectTerms | Acetylcholine receptors (nicotinic) Acetylcholinesterase Affinity Agonists Allosteric properties Alzheimer's disease Amyloid Biomarkers Biopharmaceuticals Cerebrospinal fluid Cholinergics Cholinesterase inhibitors Clinical trials Cognitive ability Drug development Effectiveness FDA approval Kinases Modulators Neurodegenerative diseases Neuromodulation Neurotransmission Protein interaction Proteins Receptors Tau protein Therapeutic targets |
Title | Targeting α7 nicotinic acetylcholine receptors and their protein interactions in Alzheimer's disease drug development |
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