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

• Published in: Bioorganic chemistry 2020-09, Vol.102, p.104050, Article 104050
• Main Authors: Jokar, Safura, Erfani, Mostafa, Bavi, Omid, Khazaei, Saeedeh, Sharifzadeh, Mohammad, Hajiramezanali, Malihe, Beiki, Davood, Shamloo, Amir
• Format: Article
• Language: English
• Subjects: Aggregation inhibition activity; Alzheimer disease; Alzheimer Disease - drug therapy; Alzheimer Disease - pathology; Amino Acid Sequence; Amyloid beta-Peptides - antagonists & inhibitors; Drug Design; Humans; Molecular docking; Molecular Docking Simulation - methods; Peptide drugs; Peptide Fragments - metabolism; β-sheet breaker
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2020.104050

[Display omitted] •The molecular interactions of designed peptides against Aβ peptide were evaluated by the molecular docking.•Targeting peptide synthesis of the Aβ aggregation was successfully synthesized.•In vitro inhibition activity studies were performed on Aβ aggregation.•The prepared peptide could be a potential therapeutic agent for inhibition of the formation and growth of Aβ aggregations in AD. 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.