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

Abstract

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-NH 2 ) as an interesting scaffold for the development of new anti-AD multitarget-directed drugs. It showed the lowest IC 50 value against hAChE reported for a peptide (0.99 � 0.02 μM) and inhibited 94.2 % � 1.2 of AChEinduced Aβ aggregation at 10 μM. Furthermore, it inhibited hBChE (IC 50 , 15.44 � 0.91 μM), showed no in vivo toxicity in brine shrimp and had shown moderated radical scavenging and Fe 2 + 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.

Harnessing the Therapeutic Potential of Peptides for Synergistic Treatment of Alzheimer’s Disease by Targeting Aβ Aggregation, Metal-Mediated Aβ Aggregation, Cholinesterase, Tau Degradation, and Oxidative Stress

“…In 2023, Sanchis et al studied the inhibitory effects of a series of designed peptides, formed by substituting aliphatic residues with aromatic ones, on human ChEs (AChE and BuChE) and AChE-induced Aβ 40 aggregation. 79 Among all peptides, W3 (Leu-Gly-Trp-Val-Ser-Lys-Gly-Lys-Leu-Leu-NH 2 ) emerged as a promising scaffold for developing MTDLs to treat AD. W3 inhibited AChE with an IC 50 value of 0.99 ± 0.02 μM and effectively hindered AChE-induced Aβ 40 aggregation (94.2 ± 1.2%).…”

“…Several MTD peptides against AD reported in this review can themselves act as guiding chemotypes for the development of potent therapeutics against AD. 46 tested in cellular model (SH-SY5Y cells) LA-GPE 47 tested in cellular model (SH-SY5Y cells) GS(HQ)H 48 tested in cellular model (SH-SY5Y cells) ZW1 51 tested in transgenic mouse model GGH 52 tested in cellular model (PC12 cells) P6 53 tested in cellular model (PC12 cells) GR 54,55 tested in cellular model (PC12 cells) and rat model GSH-LD 56 tested in cellular model (U937 cell lines) LK7-HH 58 tested in cellular model (PC12 cells) Car-LK7 59 tested in cellular model (SH-SY5Y cells) RK10 61 tested in cellular model (SH-SY5Y cells) rk10 62 tested in cellular model (SH-SY5Y cells) Glupep 66 tested in cellular model (PC12 cells) MPLT3, MPGLT 67 tested in cellular model (SH-SY5Y cells) PA 19 fCP 68 tested in cellular model (N2a cells) Semax 69 tested in cellular model (SH-SY5Y cells) DS2 70 tested in cellular model (SH-SY5Y cells) WRR, ERW 71 tested in cellular model (SH-SY5Y cells) TH006 74 tested in rat model AI 75 tested in cellular model (PC12 cells) LE6 76 tested in cellular model (PC12 cells) SLKP 77 tested in cellular model (PC12 cells) NVR 78 tested in cellular model (PC12 cells) W3 79 tested in brine shrimp RA-1 80 tested in cellular model (PC12 cells) LME-tet 85 tested in cellular model (N2a cells)…”

Acetylcholine hydrolytic activity of fibrillated β-amyloid (1–40) peptide

“…The synthesis of Aβ 40 used here was reported in a recent publication (Sanchis et al 2023). Brie y, the peptide was synthesized through FMOC solid-phase peptide synthesis using H-Rink amide ChemMatrix resin from Sigma-Aldrich.…”