Inhibition of Human Cholinesterases and in vitro β‐Amyloid Aggregation by Rationally Designed Peptides

• Published in: ChemMedChem Vol. 18; no. 12; pp. e202200691 - n/a
• Main Authors: Sanchis, Ivan, Spinelli, Roque, Dias, José, Brazzolotto, Xavier, Rietmann, Álvaro, Aimaretti, Florencia, Siano, Álvaro S.
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 15.06.2023
• Subjects: Acetylcholinesterase; Acetylcholinesterase - metabolism; Alzheimer Disease - drug therapy; Alzheimer's disease; Amyloid beta-Peptides; Biocompatibility; Butyrylcholinesterase - metabolism; Chelation; Cholinesterase; Cholinesterase inhibitors; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Drug development; Humans; Neurodegenerative diseases; Peptides; Scavenging; Structure-Activity Relationship; Toxicity; β-Amyloid; peptides; cholinesterase inhibitors; amyloid beta-peptides; Alzheimer's disease
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.202200691

The multifactorial nature of Alzheimer's disease (AD) is now widely recognized, which has increased the interest in compounds that can address more than one AD‐associated targets. Herein, we report the inhibitory activity on the human cholinesterases (acetylcholinesterase, hAChE and butyrylcholinesterase, hBChE) and on the AChE‐induced β‐amyloid peptide (Aβ) aggregation by a series of peptide derivatives designed by mutating aliphatic residues for aromatic ones. We identified peptide W3 (LGWVSKGKLL‐NH2) as an interesting scaffold for the development of new anti‐AD multitarget‐directed drugs. It showed the lowest IC50 value against hAChE reported for a peptide (0.99±0.02 μM) and inhibited 94.2 %±1.2 of AChE‐induced Aβ aggregation at 10 μM. Furthermore, it inhibited hBChE (IC50, 15.44±0.91 μM), showed no in vivo toxicity in brine shrimp and had shown moderated radical scavenging and Fe2+ chelating capabilities in previous studies. The results are in line with multiple reports showing the utility of the indole moiety for the development of cholinesterase inhibitors. A series of peptide inhibitors of the human cholinesterase enzymes was designed by mutating aliphatic residues for aromatic ones. Trp mutations highly increased the inhibitory activity of the base sequence, and the best candidate showed the most potent activity on the human acetylcholinesterase reported for a peptide (0.99±0.02 μM) and inhibited 94.2 %±1.2 of the AChE‐induced β‐amyloid peptide aggregation.