Fischer Sebastian Nils, Geyer Armin
Faculty of Chemistry, Philipps University Marburg, Hans-Meerwein-Straße 4, 35032 Marburg, Germany.
Beilstein J Org Chem. 2015 Dec 17;11:2646-53. doi: 10.3762/bjoc.11.284. eCollection 2015.
Covalent dynamic chemistry is used to mimic the first steps of the highly cooperative fibril formation of Aβ peptides. For that purpose, Aβ peptide pentapeptide boronic acids 1 and 2 were synthesized by solid-phase peptide synthesis and studied in esterification experiments with polyhydroxylated templates. The bis-hydroxylated dipeptide Hot=Tap serves as a template of adjustable degree of oligomerization which spontaneously forms boronic esters with peptides of type 1 and 2. Nuclear magnetic resonance can differentiate between regioisomeric boronic esters and identifies preferred sites of esterification on the dimeric template 9. 2-Formylphenylboronic acid (14) is used to link the parent pentapeptide Leu-Val-Phe-Phe-Ala to the template 16 to obtain threefold boronic ester 17. The miniamyloid 17 assembles from seven components by imine and boronic ester bonds between the peptides and the template. The relative orientation and spacing of the peptides mimic the assembly of peptides in Alzheimer β-amyloids.
共价动态化学被用于模拟Aβ肽高度协同的纤维形成的第一步。为此，通过固相肽合成法合成了Aβ肽五肽硼酸1和2，并在与多羟基化模板的酯化实验中进行了研究。双羟基化二肽Hot=Tap用作可调节寡聚化程度的模板，它能与1型和2型肽自发形成硼酸酯。核磁共振可以区分区域异构硼酸酯，并确定二聚体模板9上的优选酯化位点。2-甲酰基苯硼酸（14）用于将母体五肽Leu-Val-Phe-Phe-Ala连接到模板16上，以获得三倍硼酸酯17。最小淀粉样蛋白17由七个组分通过肽与模板之间的亚胺键和硼酸酯键组装而成。肽的相对取向和间距模拟了阿尔茨海默病β-淀粉样蛋白中肽的组装。
