阿尔茨海默β-淀粉样肽核心片段衍生物的合成

Synthesis of Derivatives of Peptide KLVFFs Based on the Core Segments of Alzheimer's Amyloid β-peptides

由苯丙氨酸(F)、缬氨酸(V)、亮氨酸(L)和赖氨酸(K)组成的KLVFF五肽序列是阿尔茨海默β-淀粉样肽自聚集形成纳米纤维化结构的核心片段,合成该肽段及对其分子侧链和主链结构进行修饰对研究阿尔茨海默病发病机制具有重要意义。以Fmoc-保护基缬氨酸(Fmoc V-OH)和Fmoc-保护基苯丙氨酸(Fmoc F-OH)为原料,N-羟基琥珀酰亚胺(HOSu)和二环己基碳二亚胺(DCC)为缩合剂,采用液相合成法合成了Fmoc基保护的二肽、三肽模块Fmoc FF-OH和Fmoc VLK(Boc)-OH,模块在N,N-二甲基甲酰胺(DMF)中与哌啶反应脱保护基后得到二肽、三肽NH2-FF-OH和NH2-VLK(Boc)-OH。Fmoc基保护的模块再与二肽、三肽组合、缩合及脱保护反应后,经反相高效液相色谱(RP-HPLC)分离纯化得到骨架中赖氨酸(K)的侧基由Boc保护的阿尔茨海默β-淀粉样肽核心片段肽H2N-VLK(Boc)FF-OH及H2N-FFVLK(Boc)-OH,并对目标五肽进行了核磁和质谱表征。

Peptide KLVFFs,the core segments of the amyloid β-peptide,are condensed by the phenylalanine（ F）,valine（ V）,leucine（ L）,and lysine（ K） amino acid residues. The aggregation of the amyloid β-peptide into nano-fibrils due to KLVFF peptide sequence is associated with progression of Alzheimer＇ s disease. The synthesis of peptide KLVFFs and modification of the backbones or side chain structures based on the segments is the key basis of studying the pathogenesis of Alzheimer＇s disease. In this work,Fmoc-Val-OH and Fmoc-Phe-OH as raw materials,N-hydroxy succinimide（ HOSu） and dicyclohexyl carbon imine（ DCC）as the condensing agents,have been used to synthesize the Fmoc-dipeptide and tripeptide blocks,Fmoc FF-OH and Fmoc VLK（ Boc）-OH. The blocks have been treated with piperidine in DMF to give dipeptide and tripeptide NH2-FF-OH and NH2-VLK（ Boc）-OH,respectively. Peptide H2N-VLK（ Boc） FF-OH and H2N-FFVLK（ Boc）-OH have been synthesized by condensation of corresponding dipeptide and tripeptide blocks. The peptides have been purified by reverse phase HPLC and confirmed by HNMR and ESI-MS.