Fragment-Based Discovery of an Apolipoprotein E4 (apoE4) Stabilizer
Abstract
Apolipoprotein E is a 299-residue lipid carrier protein produced in both the liver and the brain. The protein has three major isoforms denoted apoE2, apoE3, and apoE4 which differ at positions 112 and 158 and which occur at different frequencies in the human population. Genome-wide association studies indicate that the possession of two apoE4 alleles is a strong genetic risk factor for late-onset Alzheimer's disease (LOAD). In an attempt to identify a small molecule stabilizer of apoE4 function that may have utility as a therapy for Alzheimer's disease, we carried out an NMR-based fragment screen on the N-terminal domain of apoE4 and identified a benzyl amidine based fragment binder. In addition to NMR, binding was characterized using various other biophysical techniques, and a crystal structure of the bound core was obtained. Core elaboration ultimately yielded a compound that showed activity in an IL-6 and IL-8 cytokine release assay.
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ApoE4 exhibits reduced thermodynamic stability compared to ApoE3 in prior studies using purified recombinant protein.
“ApoE4 exhibits reduced thermodynamic stability compared to ApoE3, but prior characterisation has relied on purified recombinant protein”
From Utilizing a cell culture based novel cellular thermal shift assay to understand the isoform-dependent thermal stability of ApoE variants (2026) · cites this paper as [28]
The delta of the stability difference between ApoE3 and ApoE4 in BiTSA is approximately 2-3°C.
“The delta of the stability difference between ApoE3 and ApoE4 (~2-3°C) was consistent with previous reports using purified recombinant protein 28,32”
From Utilizing a cell culture based novel cellular thermal shift assay to understand the isoform-dependent thermal stability of ApoE variants (2026) · cites this paper as [28]
Multiple small molecules have been designed to correct the conformation of APOE4 so that it resembles that of APOE3 or APOE2.
“Multiple small molecules have been designed to ‘correct’ the conformation of APOE4 so that it resembles that of APOE3 or APOE2 (refs. 213–217)”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [216]
Some of these molecules have been shown to be effective in cell models, whereas others are in even earlier stages of development.
“Some of these molecules have been shown to be effective in cell models, whereas others are in even earlier stages of development216,217.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [216]
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Direct Transcriptional Effects of Apolipoprotein E
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A Monomeric, Biologically Active, Full-Length Human Apolipoprotein E
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Multifaceted roles of APOE in Alzheimer disease
Jackson, R. J., Hyman, B. T., & Serrano-Pozo, A. (2024) · Nature Reviews Neurology · doi:10.1038/s41582-024-00988-2 · Cited by 193 · see citing works
Jackson, R. J., Dierksmeier, S., Nishtar, M., Meltzer, J., Balduin, F., Beaumont, B., Fan, Z., Sergienko, E., Olson, S., Jackson, M. R., et al. (2026) · doi:10.64898/2026.06.09.730809
- Authors
- Petros, A. M., Korepanova, A., Jakob, C. G., Qiu, W., Panchal, S. C., Wang, J., Dietrich, J. D., Brewer, J. T., Pohlki, F., Kling, A., Wilcox, K., Lakics, V., Bahnassawy, L., Reinhardt, P., Partha, S. K., Bodelle, P. M., Lake, M., Charych, E. I., Stoll, V. S., Sun, C., & Mohler, E. G.
- Affiliations
- AbbVie (United States) (US)
- AbbVie (Germany) (DE)
- Corresponding author
- Petros, Andrew M.
- Mohler, Eric G.
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2019-04-01
- Volume
- 62
- Issue
- 8
- Pages
- 4120-4130
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2934814041
- Cited by
- 32
- References
- 13
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 6 · 2023: 6 · 2022: 5 · 2021: 4 · 2020: 3
- FWCI
- 2.22
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Journal of Medicinal Chemistry
- Funders
- AbbVie
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Interaction Studies and Fluorescence Analysis
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- APOE ε4, Alzheimer's disease, fragment-based drug discovery, small molecule binding, crystal structure, IL-6 release, IL-8 release, late-onset Alzheimer's disease
- MeSH terms
- Protein Domains, Alzheimer Disease, Amidines, Binding Sites, Humans, Liposomes, Magnetic Resonance Spectroscopy, Recombinant Proteins, Structure-Activity Relationship, Mutagenesis, Site-Directed, Crystallography, X-Ray, Transition Temperature, Apolipoprotein E4, Small Molecule Libraries, Drug Discovery, Molecular Dynamics Simulation
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