Stereoselective interactions of peptide inhibitors with the β-amyloid peptide
Stereoselective interactions of peptide inhibitors with the β-amyloid peptide
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DOI：
10.1074/jbc.m212694200
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发表时间：
2003-09-12
影响因子：
4.8
通讯作者：
Gervais, F
中科院分区：
文献类型：
--
作者：
Chalifour, RJ;McLaughlin, RW;Gervais, F
β -淀粉样肽（Abeta）的残基16 - 20在Abeta组装成纤维过程中起自我识别元件的作用。含有该基序的肽保留了与β相互作用的能力，在某些情况下，可以有效地抑制其组装。用d -氨基酸取代L-可以稳定这些肽，并允许它们作为阿尔茨海默病的治疗药物进行评估。在这里，我们已经评估了这种手性逆转对抑制效力的影响。在体外纤维形成实验中，KLVFFA、KKLVFFA、KFVFFA、KIVFFA和KVVFFA这五种肽的d -对映体作为抑制剂出乎意料地更有活性。圆二色性表明，D-KLVFFA更有效地阻止β采用与纤维形成相关的β片二级结构。电镜显示，D-KLVFFA对纤维形成的抑制作用也更强。利用d - β证实了异手性抑制作用，原理是对映体蛋白表现出相互的手性生化相互作用。与d - β相比，L-KLVFFA是更有效的抑制剂。最重要的是，d -肽在降低Abeta（1-40）和Abeta（1-42）对培养神经元细胞的毒性方面更有效。在未来设计以肽为基础的Abeta神经毒性和纤维形成抑制剂时，应考虑到这种未预料到的Abeta对d肽抑制剂的异手性立体选择性。
Residues 16 - 20 of the beta-amyloid peptide (Abeta) function as a self-recognition element during Abeta assembly into fibers. Peptides containing this motif retain the ability to interact with Abeta and, in some cases, potently inhibit its assembly. Replacing L- with D-amino acids could stabilize such peptides and permit their evaluation as therapeutic agents for Alzheimer's disease. Here we have assessed the effect that such a chiral reversal has on inhibitory potency. D-enantiomers of five peptides, KLVFFA, KKLVFFA, KFVFFA, KIVFFA, and KVVFFA, were unexpectedly more active as inhibitors in an in vitro fibrillogenesis assay. Circular dichroism showed that D-KLVFFA more effectively prevented Abeta adopting the beta-sheet secondary structure correlated with fibrillogenesis. Electron microscopy showed that fiber formation was also more strongly inhibited by D-KLVFFA. Heterochiral inhibition was confirmed using D-Abeta, on the principle that enantiomeric proteins exhibit reciprocal chiral biochemical interactions. With D-Abeta, L-KLVFFA was the more potent inhibitor, rather than D-KLVFFA. Most significantly, D-peptides were more potent at reducing the toxicity of both Abeta(1-40) and Abeta(1-42) toward neuronal cells in culture. This unforeseen heterochiral stereoselectivity of Abeta for D-peptide inhibitors should be considered during future design of peptide-based inhibitors of Abeta neurotoxicity and fibrillogenesis.