Design of peptide-based inhibitor agent against amyloid-β aggregation: Molecular docking, synthesis and in vitro evaluation

Jokar, S ; Sharif University of Technology | 2020

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  1. Type of Document: Article
  2. DOI: 10.1016/j.bioorg.2020.104050
  3. Publisher: Academic Press Inc , 2020
  4. Abstract:
  5. Formation of the amyloid beta (Aβ) peptide aggregations represents an indispensable role in appearing and progression of Alzheimer disease. β-sheet breaker peptides can be designed and modified with different amino acids in order to improve biological properties and binding affinity to the amyloid beta peptide. In the present study, three peptide sequences were designed based on the hopeful results of LIAIMA peptide and molecular docking studies were carried out onto the monomer and fibril structure of amyloid beta peptide using AutoDock Vina software. According to the obtained interactions and binding energy from docking, the best-designed peptide (D-GABA-FPLIAIMA) was chosen and synthesized in great yield (%96) via the Fmoc solid-phase peptide synthesis. The synthesis and purity of the resulting peptide were estimated and evaluated by Mass spectroscopy and Reversed-phase high-performance liquid chromatography (RP-HPLC) methods, respectively. Stability studies in plasma and Thioflavin T (ThT) assay were performed in order to measure the binding affinity and in vitro aggregation inhibition of Aβ peptide. The D-GABA-FPLIAIMA peptide showed good binding energy and affinity to Aβ fibrils, high stability (more than 90%) in human serum, and a reduction of 20% in inhibition of the Aβ aggregation growth. Finally, the favorable characteristics of our newly designed peptide make it a promising candidate β-sheet breaker agent for further in vivo studies. © 2020 Elsevier Inc
  6. Keywords:
  7. Aggregation inhibition activity ; Alzheimer disease ; Molecular docking ; Peptide drugs ; β-sheet breaker ; 4 aminobutyric acid ; Amyloid ; Amyloid beta protein ; Amyloid beta protein[1-42] ; Donepezil ; Monomer ; Protein inhibitor ; Synthetic peptide ; Thioflavine ; Alpha helix ; Amino acid sequence ; Smino terminal sequence ; Binding affinity ; Carboxy terminal sequence ; Conformational transition ; Crystal structure ; Drug design ; Drug efficacy ; Drug mechanism ; Drug screening ; Drug stability ; Drug synthesis ; Hydrogen bond ; Hydrophobicity ; In vitro study ; Lipophilicity ; Mass spectrometry ; Peptide synthesis ; Pharmacokinetic parameters ; Plasma ; Protein aggregation ; Protein secondary structure ; Solid phase synthesis ; Spectrofluorometry
  8. Source: Bioorganic Chemistry ; Volume 102 , September , 2020
  9. URL: https://www.sciencedirect.com/science/article/abs/pii/S004520682031347X