Department of Organic Chemistry, Faculty of Biochemistry and Biological Sciences, National University of the Littoral, Ciudad Universitaria UNL, 3000, Santa Fe, Argentina.
National Scientific and Technical Research Council (CONICET), Ministry of Science, Technology and Innovation, Godoy Cruz, 2290, Ciudad de Buenos Aires, Argentina.
ChemMedChem. 2023 Jun 15;18(12):e202200691. doi: 10.1002/cmdc.202200691. Epub 2023 Apr 19.
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-NH ) as an interesting scaffold for the development of new anti-AD multitarget-directed drugs. It showed the lowest IC 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 (IC , 15.44±0.91 μM), showed no in vivo toxicity in brine shrimp and had shown moderated radical scavenging and Fe 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.
阿尔茨海默病（AD）的多因素性质现在已被广泛认可，这增加了人们对能够针对多个与 AD 相关靶点的化合物的兴趣。在此，我们报告了一系列通过改变脂肪族残基为芳香族残基而设计的肽衍生物对人乙酰胆碱酯酶（乙酰胆碱酯酶，hAChE 和丁酰胆碱酯酶，hBChE）和 AChE 诱导的β-淀粉样肽（Aβ）聚集的抑制活性。我们确定肽 W3（LGWVSKGKLL-NH ）是开发新型抗 AD 多靶点导向药物的有趣支架。它对 hAChE 的最低 IC 值为 0.99±0.02 μM，在 10 μM 时抑制 94.2%±1.2 的 AChE 诱导的 Aβ聚集。此外，它抑制 hBChE（IC ，15.44±0.91 μM），在盐水虾中没有显示出体内毒性，并且在以前的研究中已经显示出适度的自由基清除和 Fe 螯合能力。这些结果与多项表明吲哚部分对开发胆碱酯酶抑制剂有用的报告一致。
