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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2024-12-01
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| author | Marilena K. Theodoropoulou Konstantina D. Vraila Nikos C. Papandreou Georgia I. Nasi Vassiliki A. Iconomidou |
| author_facet | Marilena K. Theodoropoulou Konstantina D. Vraila Nikos C. Papandreou Georgia I. Nasi Vassiliki A. Iconomidou |
| author_sort | Marilena K. Theodoropoulou |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-34065866ef1946eeaf83e135304c59f5 |
| institution | Kabale University |
| issn | 2218-273X |
| language | English |
| publishDate | 2024-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj-art-34065866ef1946eeaf83e135304c59f52025-01-24T13:24:54ZengMDPI AGBiomolecules2218-273X2024-12-011512810.3390/biom15010028Co-Localized in Amyloid Plaques Cathepsin B as a Source of Peptide Analogs Potential Drug Candidates for Alzheimer’s DiseaseMarilena K. Theodoropoulou0Konstantina D. Vraila1Nikos C. Papandreou2Georgia I. Nasi3Vassiliki A. Iconomidou4Section of Cell Biology and Biophysics, Department of Biology, School of Sciences, National and Kapodistrian University of Athens, Panepistimiopolis, 157 01 Athens, GreeceSection of Cell Biology and Biophysics, Department of Biology, School of Sciences, National and Kapodistrian University of Athens, Panepistimiopolis, 157 01 Athens, GreeceSection of Cell Biology and Biophysics, Department of Biology, School of Sciences, National and Kapodistrian University of Athens, Panepistimiopolis, 157 01 Athens, GreeceSection of Cell Biology and Biophysics, Department of Biology, School of Sciences, National and Kapodistrian University of Athens, Panepistimiopolis, 157 01 Athens, GreeceSection of Cell Biology and Biophysics, Department of Biology, School of Sciences, National and Kapodistrian University of Athens, Panepistimiopolis, 157 01 Athens, GreeceAlzheimer’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.https://www.mdpi.com/2218-273X/15/1/28Alzheimer’s diseaseCathepsin Baggregation-prone regionsamyloid-<i>β</i>A<i>β</i>molecular dynamics |
| spellingShingle | Marilena K. Theodoropoulou Konstantina D. Vraila Nikos C. Papandreou Georgia I. Nasi Vassiliki A. Iconomidou Co-Localized in Amyloid Plaques Cathepsin B as a Source of Peptide Analogs Potential Drug Candidates for Alzheimer’s Disease Biomolecules Alzheimer’s disease Cathepsin B aggregation-prone regions amyloid-<i>β</i> A<i>β</i> molecular dynamics |
| title | Co-Localized in Amyloid Plaques Cathepsin B as a Source of Peptide Analogs Potential Drug Candidates for Alzheimer’s Disease |
| title_full | Co-Localized in Amyloid Plaques Cathepsin B as a Source of Peptide Analogs Potential Drug Candidates for Alzheimer’s Disease |
| title_fullStr | Co-Localized in Amyloid Plaques Cathepsin B as a Source of Peptide Analogs Potential Drug Candidates for Alzheimer’s Disease |
| title_full_unstemmed | Co-Localized in Amyloid Plaques Cathepsin B as a Source of Peptide Analogs Potential Drug Candidates for Alzheimer’s Disease |
| title_short | Co-Localized in Amyloid Plaques Cathepsin B as a Source of Peptide Analogs Potential Drug Candidates for Alzheimer’s Disease |
| title_sort | co localized in amyloid plaques cathepsin b as a source of peptide analogs potential drug candidates for alzheimer s disease |
| topic | Alzheimer’s disease Cathepsin B aggregation-prone regions amyloid-<i>β</i> A<i>β</i> molecular dynamics |
| url | https://www.mdpi.com/2218-273X/15/1/28 |
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