Drug discovery for Alzheimer's disease targeting the transmembrane domain of amyloid precursor protein (AAPTM).

Authors
Eden, Angela Bailey
ORCID
https://orcid.org/0000-0002-8427-8098
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Other Contributors
Gross, Richard A.
Colón, Wilfredo
Kumar, Sunil
Wang, Chunyu
Issue Date
2022-08
Keywords
Chemistry
Degree
PhD
Terms of Use
Attribution-NonCommercial-NoDerivs 3.0 United States
This electronic version is a licensed copy owned by Rensselaer Polytechnic Institute (RPI), Troy, NY. Copyright of original work retained by author.
Full Citation
Abstract
Alzheimer’s Disease (AD) is a neurological disease currently affecting close to 6 million Americans (3). A major neuropathological hallmark of AD is the presence of senile plaques in the cerebral cortex and hippocampus (3). Senile plaques (amyloid plaques) are mainly composed of extracellular aggregates of amyloid β-peptides (Aβs); it has been hypothesized that Aβ deposition initiates a pathological cascade resulting in cognitive decline characteristic of AD (9-11). γ-secretase (GS) cleaves amyloid precursor protein (APP) in its transmembrane domain generating Aβ40 and Aβ42 that aggregate into the insoluble aggregates of senile plaques (5,11). GS has been a target of anti-AD drug discovery projects with limited success (23-25). Two broad spectrum GS inhibitors (GSIs), avagacestat and semagacestat, failed due to worsening cognition in patients in addition to other serious adverse effects largely attributable to the 90 endogenous substrates of GS (23-25). Despite GSIs’ failure, there is compelling evidence that Aβ is a causative agent in AD, including but not limited to: human genetics of familial AD (FAD) (12-14) and Down’s syndrome (30-31). To circumvent issues from GS inhibition we aimed to target the GS substrate in the amyloidogenic pathway, the transmembrane domain of APP (APPTM). Multiple screening methods resulted in two different binders of APPTM that inhibited APPTM cleavage by GS or presenilin homolog (PSH), 6H8 and N1. 6H8, a covalent modifier of APPTM found in a fragment library, modifies C-terminal lysines in APPTM via a Michael addition mechanism. While N1, a non-covalent modifier found by DNA encoded library screen, binds to APPTM though both hydrophobic and electrostatic interactions. 6H8 and N1 inhibit cleavage of APPTM with IC50 values in the low micromolar and tens of nanomolar ranges, respectively. 6H8 may be engineered into a targeted covalent inhibitor while N1, with nanomolar efficacy, is a promising lead compound for lowering amyloid load for managing AD.
Description
August 2022
School of Science
Department
Dept. of Chemistry and Chemical Biology
Publisher
Rensselaer Polytechnic Institute, Troy, NY
Relationships
Rensselaer Theses and Dissertations Online Collection
Access
CC BY-NC-ND. Users may download and share copies with attribution in accordance with a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 license. No commercial use or derivatives are permitted without the explicit approval of the author.