Structure-function relationships for inhibitors of β-amyloid toxicity containing the recognition sequence KLVFF
Structure-function relationships for inhibitors of β-amyloid toxicity containing the recognition sequence KLVFF
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DOI：
10.1021/bi002734u
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发表时间：
2001-07-03
期刊：
影响因子：
2.9
通讯作者：
Murphy, RM
中科院分区：
文献类型：
--
作者：
Lowe, TL;Strzelec, A;Murphy, RM
β-淀粉样蛋白（Aβ）是阿尔茨海默病斑块的主要蛋白质成分，当聚集成原纤维时具有神经毒性。我们设计了一种模块化策略来生成抑制 A β 毒性的化合物。这些化合物含有一个旨在与 Aβ 结合的识别元件，与一个旨在干扰 Aβ 聚集的破坏元件相连。在此策略的基础上，合成了一种杂合肽，其中序列 KLVFF（A β 的残基 16-20）作为识别元件，赖氨酸六聚体作为破坏元件：该化合物在体外保护细胞免受 A β 毒性[Pallitto，M. M.，等人。 (1999) 生物化学 38, 3570]。为了确定是否可以减少破坏元件的长度，合成了包含 KLVFF 识别元件和 1 至 6 个赖氨酸序列作为破坏元件的肽。所有化合物都增强了 Aβ 的聚集速率，且随着破坏元件中赖氨酸数量的增加，效果的程度也随之增加。使用依次含有三个或摩尔赖氨酸破坏元素的化合物可以实现最大程度的针对 Aβ 毒性的保护。具有阴离子破坏元素的肽 KLVFFEEEE 在细胞毒性和生物物理测定中具有与 KLVFFKKKK 相似的活性，而具有中性极性破坏元素的肽 KLVFFSSSS 则无效。即使抑制剂：Aβ 摩尔比为 1:100，保护性化合物也能保留活性，这使得这些化合物成为迄今为止报道的最有效的 Aβ 毒性抑制剂。这些结果为设计更有效的 Aβ 毒性抑制剂并阐明其作用机制提供了重要的见解。
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.