Affiliation:
1. Department of Organic Chemistry Faculty of Biochemistry and Biological Sciences National University of the Littoral Ciudad Universitaria UNL 3000 Santa Fe Argentina
2. National Scientific and Technical Research Council (CONICET) Ministry of Science, Technology and Innovation Godoy Cruz 2290 Ciudad de Buenos Aires Argentina
3. Département de Toxicologie et Risques Chimiques Institut de Recherche Biomédicale des Armées (IRBA) 1 Place du Général Valérie André 91220 Brétigny-sur-Orge France
Abstract
AbstractThe 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.
Subject
Organic Chemistry,General Pharmacology, Toxicology and Pharmaceutics,Molecular Medicine,Drug Discovery,Biochemistry,Pharmacology
Cited by
2 articles.
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