Rationally Designed Pentapeptide Analogs of Aβ19–23 Fragment as Potent Inhibitors of Aβ42 Aggregation
Amyloid beta (Aβ42 and Aβ40) aggregation, along with neurofibrillary tangles, is one of the major neurotoxic events responsible for the onset of Alzheimer’s disease. Many potent peptide-based inhibitors mainly focusing on central hydrophobic core Aβ16–20 (KLVFF) have been reported in recent years. H...
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2025-05-01
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| author | Sachin B. Baravkar Yan Lu Qi Zhao Hongying Peng Weilie Zhou Song Hong |
| author_facet | Sachin B. Baravkar Yan Lu Qi Zhao Hongying Peng Weilie Zhou Song Hong |
| author_sort | Sachin B. Baravkar |
| collection | DOAJ |
| description | Amyloid beta (Aβ42 and Aβ40) aggregation, along with neurofibrillary tangles, is one of the major neurotoxic events responsible for the onset of Alzheimer’s disease. Many potent peptide-based inhibitors mainly focusing on central hydrophobic core Aβ16–20 (KLVFF) have been reported in recent years. Herein, we report pentapeptides <b>1</b>–<b>4</b>, based on the β-turn-inducing fragment Aβ19–23 (FFAED). The synthesis of peptides <b>1</b>–<b>4</b> was carried out using Fmoc/tBu-based solid-phase peptide synthesis technique, and it was found that pentapeptide <b>3</b> potently inhibit the aggregation propensity of Aβ42, when incubated with it at 37 °C for 48 h. The aggregation inhibition study was conducted using thioflavin T-based fluorescence assay and circular dichroism spectroscopy, and supported by transmission electron microscope imaging. The conformational change on the aggregation of Aβ42 and aggregation inhibition by peptides <b>1</b>–<b>4</b> was further evaluated using <sup>1</sup>H–<sup>15</sup>N HSQC NMR spectroscopy. The results demonstrated that the most potent analog, peptide <b>3</b>, effectively disrupts the aggregation process. This study is the first to demonstrate that an Aβ19–23 fragment mimic can disrupt the aggregation propensity of Aβ42. |
| format | Article |
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| institution | Kabale University |
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| language | English |
| publishDate | 2025-05-01 |
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| spelling | doaj-art-1ae079e6b6864a5d92716b37ccc0f6c02025-08-20T03:52:57ZengMDPI AGMolecules1420-30492025-05-01309207110.3390/molecules30092071Rationally Designed Pentapeptide Analogs of Aβ19–23 Fragment as Potent Inhibitors of Aβ42 AggregationSachin B. Baravkar0Yan Lu1Qi Zhao2Hongying Peng3Weilie Zhou4Song Hong5Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health, New Orleans, LA 70112, USANeuroscience Center of Excellence, School of Medicine, Louisiana State University Health, New Orleans, LA 70112, USANMR Laboratory, Department of Chemistry, Tulane University, New Orleans, LA 70115, USADepartment of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH 45221, USADepartment of Physics & Adavanced Materials Research Institute (AMRI), University of New Orleans, New Orleans, LA 70148, USANeuroscience Center of Excellence, School of Medicine, Louisiana State University Health, New Orleans, LA 70112, USAAmyloid beta (Aβ42 and Aβ40) aggregation, along with neurofibrillary tangles, is one of the major neurotoxic events responsible for the onset of Alzheimer’s disease. Many potent peptide-based inhibitors mainly focusing on central hydrophobic core Aβ16–20 (KLVFF) have been reported in recent years. Herein, we report pentapeptides <b>1</b>–<b>4</b>, based on the β-turn-inducing fragment Aβ19–23 (FFAED). The synthesis of peptides <b>1</b>–<b>4</b> was carried out using Fmoc/tBu-based solid-phase peptide synthesis technique, and it was found that pentapeptide <b>3</b> potently inhibit the aggregation propensity of Aβ42, when incubated with it at 37 °C for 48 h. The aggregation inhibition study was conducted using thioflavin T-based fluorescence assay and circular dichroism spectroscopy, and supported by transmission electron microscope imaging. The conformational change on the aggregation of Aβ42 and aggregation inhibition by peptides <b>1</b>–<b>4</b> was further evaluated using <sup>1</sup>H–<sup>15</sup>N HSQC NMR spectroscopy. The results demonstrated that the most potent analog, peptide <b>3</b>, effectively disrupts the aggregation process. This study is the first to demonstrate that an Aβ19–23 fragment mimic can disrupt the aggregation propensity of Aβ42.https://www.mdpi.com/1420-3049/30/9/2071Alzheimer’s diseaseamyloid beta aggregation inhibitorpentapeptidescircular dichroismthioflavin T fluorescence assaytransmission electron microscopy TEM |
| spellingShingle | Sachin B. Baravkar Yan Lu Qi Zhao Hongying Peng Weilie Zhou Song Hong Rationally Designed Pentapeptide Analogs of Aβ19–23 Fragment as Potent Inhibitors of Aβ42 Aggregation Molecules Alzheimer’s disease amyloid beta aggregation inhibitor pentapeptides circular dichroism thioflavin T fluorescence assay transmission electron microscopy TEM |
| title | Rationally Designed Pentapeptide Analogs of Aβ19–23 Fragment as Potent Inhibitors of Aβ42 Aggregation |
| title_full | Rationally Designed Pentapeptide Analogs of Aβ19–23 Fragment as Potent Inhibitors of Aβ42 Aggregation |
| title_fullStr | Rationally Designed Pentapeptide Analogs of Aβ19–23 Fragment as Potent Inhibitors of Aβ42 Aggregation |
| title_full_unstemmed | Rationally Designed Pentapeptide Analogs of Aβ19–23 Fragment as Potent Inhibitors of Aβ42 Aggregation |
| title_short | Rationally Designed Pentapeptide Analogs of Aβ19–23 Fragment as Potent Inhibitors of Aβ42 Aggregation |
| title_sort | rationally designed pentapeptide analogs of aβ19 23 fragment as potent inhibitors of aβ42 aggregation |
| topic | Alzheimer’s disease amyloid beta aggregation inhibitor pentapeptides circular dichroism thioflavin T fluorescence assay transmission electron microscopy TEM |
| url | https://www.mdpi.com/1420-3049/30/9/2071 |
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