4.5 Article

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

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CHEMMEDCHEM
卷 18, 期 12, 页码 -

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WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.202200691

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Alzheimer's disease; cholinesterase inhibitors; amyloid beta-peptides; peptides

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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.
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.

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