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 beta-amyloid peptide (A beta) 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 mu M) and inhibited 94.2 %+/- 1.2 of AChE-induced A beta aggregation at 10 mu M. Furthermore, it inhibited hBChE (IC50, 15.44 +/- 0.91 mu M), 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.

Automated summary

We report a series of peptide derivatives with inhibitory activity on human cholinesterases and AChE-induced β-amyloid peptide aggregation. Peptide W3 was identified as an interesting scaffold for the development of new anti-AD multitarget-directed drugs, with the lowest IC50 value against hAChE and inhibition of AChE-induced Aβ aggregation. It also showed inhibitory activity on hBChE, no in vivo toxicity, and moderate radical scavenging and Fe2+ chelating capabilities.