An Overview of β-Amyloid Cleaving Enzyme 1 (Bace1) in Alzheimer's Disease Therapy Elucidating its Exosite-Binding Antibody and Allosteric Inhibitor

(E-pub Abstract Ahead of Print)

Author(s): Samuel C. Ugbaja, Monsurat Lawal*, Hezekiel Kumalo*

Journal Name: Current Medicinal Chemistry

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Over decades of its identification, numerous past and ongoing researches have focused on the therapeutic roles of β-amyloid cleaving enzyme 1 (BACE1) as a target in treating Alzheimer's disease (AD). Although the initial BACE1 inhibitors at phase-3 clinical trials tremendously reduced β-amyloid-associated plaques in patients with AD, the researchers eventually discontinued the tests due to the lack of potency. This discontinuation has resulted in limited drug development and discovery targeted at BACE1, despite the high demand for dementia and AD therapies. It is, therefore, imperative to describe the detailed underlying biological basis of the BACE1 therapeutic option in neurological diseases. Herein, we highlight BACE1 bioactivity, genetic properties, and role in neurodegenerative therapy. We review research contributions to BACE1 exosite-binding antibody and allosteric inhibitor development as AD therapies. The review also covers BACE1 biological function, the disease-associated mechanisms, and the enzyme conditions for amyloid precursor protein sites splitting. Based on the present review, we suggest further studies on anti-BACE1 exosite antibodies and BACE1 allosteric inhibitors. Non-active site inhibition might be the way forward to BACE1 therapy in Alzheimer's neurological disorder.

Keywords: BACE1 biological properties, Alzheimer's disease, BACE1 exosites antibody, BACE1 substrates, Gene expression, Allosteric inhibitors

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(E-pub Abstract Ahead of Print)
DOI: 10.2174/0929867328666210608145357
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