Co-Localized in Amyloid Plaques Cathepsin B as a Source of Peptide Analogs Potential Drug Candidates for Alzheimer’s Disease
Alzheimer’s disease (AD) is a complex neurodegenerative disorder characterized by extracellular amyloid plaques, predominantly consisting of amyloid-<i>β</i> (A<i>β</i>) peptides. The oligomeric form of A<i>β</i> is acknowledged as the most neurotoxic, propelling...
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| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2024-12-01
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| Series: | Biomolecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2218-273X/15/1/28 |
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| Summary: | Alzheimer’s disease (AD) is a complex neurodegenerative disorder characterized by extracellular amyloid plaques, predominantly consisting of amyloid-<i>β</i> (A<i>β</i>) peptides. The oligomeric form of A<i>β</i> is acknowledged as the most neurotoxic, propelling the pathological progression of AD. Interestingly, besides A<i>β</i>, other proteins are co-localized within amyloid plaques. Peptide analogs corresponding to the “aggregation-prone” regions (APRs) of these proteins could exhibit high-affinity binding to A<i>β</i> and significant inhibitory potential against the A<i>β</i> oligomerization process. The peptide analogs of co-localized protease, Cathepsin B, may act as such potent inhibitors. In silico studies on the complexes of the oligomeric state of A<i>β</i> and Cathepsin B peptide analogs were performed utilizing molecular docking and molecular dynamics simulations, revealing that these analogs disrupt the <i>β</i>-sheet-rich core of A<i>β</i> oligomers, a critical structural feature of their stability. Of the four peptide analogs evaluated, two demonstrated considerable potential by effectively destabilizing oligomers while maintaining low self-aggregation propensity, i.e., a crucial consideration for therapeutic safety. These findings point out the potential of APR-derived peptide analogs from co-localized proteins as innovative agents against AD, paving the way for further exploration in peptide-based therapeutic development. |
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| ISSN: | 2218-273X |