Ruthenium(III) complexes with imidazole ligands that modulate the aggregation of the amyloid-β peptide via hydrophobic interactions
Published by Elsevier Inc..
Alzheimer's disease (AD) is the most common form of dementia, characterized by extracellular protein deposits, comprised primarily of the peptide amyloid-beta (Aβ), are a pathological indicator of the disease. Commonly known as Aβ plaques, these deposits contain a relatively high concentration of metals, making metallotherapeutics uniquely suited to target soluble Aβ, thereby limiting its aggregation and cytotoxicity. Ruthenium-based complexes are promising candidates for advancement, as the complex PMRU20 (2-aminothiazolium [trans-RuCl4(2-aminothiazole)2]) and several thiazole-based derivatives were found to prevent the aggregation of Aβ, with hydrogen-bonding functional groups improving their performance. Further investigation into the impact of the heteroatom in the azole ring on the activity of Ru complexes was achieved through the synthesis and evaluation of a small set of imidazole-based compounds. The ability of the complexes to prevent the aggregation of Aβ was determined where the same sample was subjected to analysis by three complementary methods: ThT fluorescence, dynamic light scattering (DLS), and transmission electron microscopy (TEM). It was found that hydrophobic interactions, along with hydrogen-bonding via the imidazole nitrogen heteroatom, promoted interactions with the Aβ peptide, thereby limiting its aggregation. Furthermore, it was found that having rapid and sequential exchange proved detrimental as it resulted in a decreased association with Aβ. These results highlight important considerations between a balance of intermolecular interactions and ligand exchange kinetics in the design of further therapeutic candidates.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:214 |
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| Enthalten in: |
Journal of inorganic biochemistry - 214(2021) vom: 15. Jan., Seite 111303 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Yawson, Gideon K [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 01.09.2021 Date Revised 01.09.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.jinorgbio.2020.111303 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM317346113 |
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| 100 | 1 | |a Yawson, Gideon K |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Ruthenium(III) complexes with imidazole ligands that modulate the aggregation of the amyloid-β peptide via hydrophobic interactions |
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| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Published by Elsevier Inc. | ||
| 520 | |a Alzheimer's disease (AD) is the most common form of dementia, characterized by extracellular protein deposits, comprised primarily of the peptide amyloid-beta (Aβ), are a pathological indicator of the disease. Commonly known as Aβ plaques, these deposits contain a relatively high concentration of metals, making metallotherapeutics uniquely suited to target soluble Aβ, thereby limiting its aggregation and cytotoxicity. Ruthenium-based complexes are promising candidates for advancement, as the complex PMRU20 (2-aminothiazolium [trans-RuCl4(2-aminothiazole)2]) and several thiazole-based derivatives were found to prevent the aggregation of Aβ, with hydrogen-bonding functional groups improving their performance. Further investigation into the impact of the heteroatom in the azole ring on the activity of Ru complexes was achieved through the synthesis and evaluation of a small set of imidazole-based compounds. The ability of the complexes to prevent the aggregation of Aβ was determined where the same sample was subjected to analysis by three complementary methods: ThT fluorescence, dynamic light scattering (DLS), and transmission electron microscopy (TEM). It was found that hydrophobic interactions, along with hydrogen-bonding via the imidazole nitrogen heteroatom, promoted interactions with the Aβ peptide, thereby limiting its aggregation. Furthermore, it was found that having rapid and sequential exchange proved detrimental as it resulted in a decreased association with Aβ. These results highlight important considerations between a balance of intermolecular interactions and ligand exchange kinetics in the design of further therapeutic candidates | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 4 | |a Alzheimer's disease | |
| 650 | 4 | |a Amyloid-beta peptide | |
| 650 | 4 | |a Dynamic light scattering | |
| 650 | 4 | |a Ruthenium(III) therapeutics | |
| 650 | 4 | |a ThT fluorescence | |
| 650 | 4 | |a Transmission Electron microscopy | |
| 650 | 7 | |a Amyloid beta-Peptides |2 NLM | |
| 650 | 7 | |a Coordination Complexes |2 NLM | |
| 650 | 7 | |a Imidazoles |2 NLM | |
| 650 | 7 | |a Protein Aggregates |2 NLM | |
| 650 | 7 | |a imidazole |2 NLM | |
| 650 | 7 | |a 7GBN705NH1 |2 NLM | |
| 650 | 7 | |a Ruthenium |2 NLM | |
| 650 | 7 | |a 7UI0TKC3U5 |2 NLM | |
| 700 | 1 | |a Huffman, Samantha E |e verfasserin |4 aut | |
| 700 | 1 | |a Fisher, Samuel S |e verfasserin |4 aut | |
| 700 | 1 | |a Bothwell, Paige J |e verfasserin |4 aut | |
| 700 | 1 | |a Platt, David C |e verfasserin |4 aut | |
| 700 | 1 | |a Jones, Marjorie A |e verfasserin |4 aut | |
| 700 | 1 | |a Ferrence, Gregory M |e verfasserin |4 aut | |
| 700 | 1 | |a Hamaker, Christopher G |e verfasserin |4 aut | |
| 700 | 1 | |a Webb, Michael I |e verfasserin |4 aut | |
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