毒性
随机六聚体
肽
化学
生物化学
序列(生物学)
生物物理学
生物
有机化学
作者
Tao L. Lowe,Andrea Strzelec,Laura L. Kiessling,Regina M. Murphy
出处
期刊:Biochemistry
[American Chemical Society]
日期:2001-06-07
卷期号:40 (26): 7882-7889
被引量:196
摘要
β-Amyloid (Aβ), the primary protein component of Alzheimer's plaques, is neurotoxic when aggregated into fibrils. We have devised a modular strategy for generating compounds that inhibit Aβ toxicity. These compounds contain a recognition element, designed to bind to Aβ, linked to a disrupting element, designed to interfere with Aβ aggregation. On the basis of this strategy, a hybrid peptide was synthesized with the sequence KLVFF (residues 16−20 of Aβ) as the recognition element and a lysine hexamer as the disrupting element; this compound protects cells in vitro from Aβ toxicity [Pallitto, M. M., et al. (1999) Biochemistry 38, 3570]. To determine if the length of the disrupting element could be reduced, peptides were synthesized that contained the KLVFF recognition element and a sequence of one to six lysines as disrupting elements. All compounds enhanced the rate of aggregation of Aβ, with the magnitude of the effect increasing as the number of lysines in the disrupting element increased. The greatest level of protection against Aβ toxicity was achieved with compounds containing disrupting elements of three or more lysines in sequence. A peptide with an anionic disrupting element, KLVFFEEEE, had activity similar to that of KLVFFKKKK, in both cellular toxicity and biophysical assays, whereas a peptide with a neutral polar disrupting element, KLVFFSSSS, was ineffective. Protective compounds retained activity even at an inhibitor:Aβ molar ratio of 1:100, making these some of the most effective inhibitors of Aβ toxicity reported to date. These results provide critical insight needed to design more potent inhibitors of Aβ toxicity and to elucidate their mechanism of action.
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