期刊
BIOCHEMISTRY
卷 40, 期 26, 页码 7882-7889出版社
AMER CHEMICAL SOC
DOI: 10.1021/bi002734u
关键词
-
资金
- NINDS NIH HHS [NS37728] Funding Source: Medline
beta -Amyloid (A beta), 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 A beta toxicity. These compounds contain a recognition element, designed to bind to A beta, linked to a disrupting element, designed to interfere with A beta aggregation. On the basis of this strategy, a hybrid peptide was synthesized with the sequence KLVFF (residues 16-20 of A beta) as the recognition element and a lysine hexamer as the disrupting element: this compound protects cells in vitro from A beta 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 A beta, with the magnitude of the effect increasing as the number of lysines in the disrupting element increased. The greatest level of protection against A beta toxicity was achieved with compounds containing disrupting elements of three or mole 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:A beta molar ratio of 1:100, making these some of the most effective inhibitors of A beta toxicity reported to date. These results provide critical insight needed to design more potent inhibitors of A beta toxicity and to elucidate their mechanism of action.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据