Design of Gallic Acid–Glutamine Conjugate and Chemical Implications for Its Potency Against Alzheimer’s Amyloid‑β Fibrillogenesis

• Published in: Bioconjugate chemistry Vol. 33; no. 4; pp. 677 - 690
• Main Authors: Xu, Shaoying, Sun, Yan, Dong, Xiaoyan
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 20.04.2022; Amer Chemical Soc
• Subjects: Alzheimer Disease - drug therapy; Alzheimer's disease; Amyloid; Amyloid beta-Peptides - chemistry; Binding sites; Biochemical Research Methods; Biochemistry & Molecular Biology; Bridges; Carboxyl group; Chemistry; Chemistry, Multidisciplinary; Chemistry, Organic; Conjugates; Electrostatic properties; Epigallocatechin gallate; Fibrillogenesis; Gallic acid; Gallic Acid - pharmacology; Glutamic acid; Glutamine; Humans; Hydrogen; Hydrogen bonding; Hydrophobicity; Ions; Life Sciences & Biomedicine; Life span; Molecular Dynamics Simulation; Nematodes; Neurodegenerative diseases; Peptide Fragments - metabolism; Physical Sciences; Science & Technology; Thermodynamics; β-Amyloid; ISOTHERMAL TITRATION CALORIMETRY; MOLECULAR-DYNAMICS; CAENORHABDITIS-ELEGANS; PEPTIDE 42; PROTEIN; MECHANISM; DISEASE; BINDING MODELS; AGGREGATION; THIOFLAVIN T
• ISSN: 1043-1802; 1520-4812
• DOI: 10.1021/acs.bioconjchem.2c00073

Epigallocatechin-3-gallate (EGCG) has been widely recognized as a potent inhibitor of Alzheimer’s amyloid-β (Aβ) fibrillogenesis. We found that gallic acid (GA) has superior inhibitory effects over EGCG at the same mass concentrations and assumed the pivotal role of the carboxyl group in GA. Therefore, we designed five GA-derivatives to investigate the significance of carboxyl groups in modulating Aβ fibrillogenesis, including carboxyl-amidated GA (GA-NH2), GA-glutamic acid conjugate (GA-E), and GA-E derivatives with amidated either of the two carboxyl groups (GA-Q and GA-E-NH2) or with two amidated-carboxyl groups (GA-Q-NH2). Intriguingly, only GA-Q shows significantly stronger potency than GA and extends the life span of the AD transgenic nematode by over 30%. Thermodynamic studies reveal that GA-Q has a strong binding affinity for Aβ42 with two binding sites, one stronger (site 1, K a1 = 3.1 × 106 M–1) and the other weaker (site 2, K a2 = 0.8 × 106 M–1). In site 1, hydrogen bonding, electrostatic interactions, and hydrophobic interactions all have contributions, while in site 2, only hydrogen bonding and electrostatic interactions work. The two sites are confirmed by molecular simulations, and the computations specified the key residues. GA-Q has strong binding to Asp23, Gly33, Gly38, Ala30, Ile31, and Leu34 via hydrogen bonding and electrostatic interactions, while it interacts with Phe19, Ala21 Gly25, and Asn27 via hydrophobic interactions. Consequently, GA-Q destroys Asp23-Lys28 salt bridges and restricts β-sheet/bridge structures. The thermodynamic and molecular insight into the GA-Q functions on inhibiting Aβ fibrillogenesis would pave a new way to the design of potent molecules against Alzheimer’s amyloid.