Pseudopeptide Amyloid Aggregation Inhibitors: In Silico, Single Molecule and Cell Viability Studies.
Int J Mol Sci
; 22(3)2021 Jan 21.
Article
em En
| MEDLINE
| ID: mdl-33494369
ABSTRACT
Neurodegeneration in Alzheimer's disease (AD) is defined by pathology featuring amyloid-ß (Aß) deposition in the brain. Aß monomers themselves are generally considered to be nontoxic, but misfold into ß-sheets and aggregate to form neurotoxic oligomers. One suggested strategy to treat AD is to prevent the formation of toxic oligomers. The SG inhibitors are a class of pseudopeptides designed and optimized using molecular dynamics (MD) simulations for affinity to Aß and experimentally validated for their ability to inhibit amyloid-amyloid binding using single molecule force spectroscopy (SMFS). In this work, we provide a review of our previous MD and SMFS studies of these inhibitors and present new cell viability studies that demonstrate their neuroprotective effects against Aß(1-42) oligomers using mouse hippocampal-derived HT22 cells. Two of the tested SG inhibitors, predicted to bind Aß in anti-parallel orientation, demonstrated neuroprotection against Aß(1-42). A third inhibitor, predicted to bind parallel to Aß, was not neuroprotective. Myristoylation of SG inhibitors, intended to enhance delivery across the blood-brain barrier (BBB), resulted in cytotoxicity. This is the first use of HT22 cells for the study of peptide aggregation inhibitors. Overall, this work will inform the future development of peptide aggregation inhibitors against Aß toxicity.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Peptídeos
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Proteínas Amiloidogênicas
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Agregação Patológica de Proteínas
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Agregados Proteicos
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Amiloide
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article