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

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.