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

SANCHIS, IVAN; SPINELLI, ROQUE; DIAS, JOSÉ; BRAZZOLOTTO, XAVIER; RIETMANN, ÁLVARO; AIMARETTI, FLORENCIA; SIANO, ÁLVARO S.

CHEMMEDCHEM

WILEY-V C H VERLAG GMBH

Año: 2023

1860-7179

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.