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Cited by 132Alzheimer's disease research and treatmentsCholinesterase and Neurodegenerative DiseasesHeat shock proteins research

Small-Molecule Structure Correctors Target Abnormal Protein Structure and Function: Structure Corrector Rescue of Apolipoprotein E4–Associated Neuropathology: Miniperspective

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Mahley, Robert W., Huang, Yadong·2012·Journal of Medicinal Chemistry
DOI 10.1021/jm3008618PMC PMC4904786
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Abstract

An attractive strategy to treat proteinopathies (diseases caused by malformed or misfolded proteins) is to restore protein function by inducing proper three-dimensional structure. We hypothesized that this approach would be effective in reversing the detrimental effects of apolipoprotein (apo) E4, the major allele that significantly increases the risk of developing Alzheimer's disease and other neurodegenerative disorders. ApoE4's detrimental effects result from its altered protein conformation ("domain interaction"), making it highly susceptible to proteolytic cleavage and the generation of neurotoxic fragments. Here, we review apoE structure and function and how apoE4 causes neurotoxicity, and describe the identification of potent small-molecule-based "structure correctors" that induce proper apoE4 folding. SAR studies identified a series of small molecules that significantly reduced apoE4's neurotoxic effects in cultured neurons and a series that reduced apoE4 fragment levels in vivo, providing proof-of-concept for our approach. Structure-corrector-based therapies could prove to be highly effective for the treatment of many protein-misfolding diseases.

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Authors
Mahley, R. W., & Huang, Y.
Affiliations
Gladstone Institutes (US)
Corresponding author
Mahley, Robert W.
ORCID
Venue
Journal of Medicinal Chemistry
Publisher
American Chemical Society (ACS)
Published
2012-10-05
Volume
55
Issue
21
Pages
8997-9008
ISSN
  • 0022-2623 (ISSN-L)
  • 1520-4804
DOI
10.1021/jm3008618
PMC
PMC4904786
OpenAlex
W2056145534
Cited by
132
References
19
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FWCI
1.08
Type
journal article
Language
en
Open access
Locations
  • Journal of Medicinal Chemistry (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • American Academy of Arts and Sciences
  • Gladstone Institutes
  • Peking Union Medical College
  • Qingdao University
  • National Institutes of Health
  • National Institute on Aging (P01AG022074)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
Keywords
APOE ε4, protein misfolding, proteinopathies, Alzheimer's disease, small molecule drugs, structure-activity relationship, neurotoxicity, protein folding, neurodegenerative diseases
MeSH terms
Alzheimer Disease, Animals, Brain Injuries, Endoplasmic Reticulum, Golgi Apparatus, Humans, Models, Molecular, Neurons, Protein Conformation, Structure-Activity Relationship, Protein Folding, Protein Transport, Lipid Metabolism, Apolipoprotein E4, Proteostasis Deficiencies, Molecular Targeted Therapy

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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