Assembly of synthetic Aβ miniamyloids on polyol templates

Abstract

SummaryCovalent 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.

Reversible Boronic Ester Formation of Ribopyranosylated Glycopeptides

“…NMR is the preferred analytical method which simultaneously quantifies the boronic ester formation and allows a detailed conformational analysis of the glycopeptide. [37,38] Each peptide (8)(9)(10)(11)(12)(13) and an equimolar amount of pyrene boronic acid were mixed in DMSO-d 6 to obtain the corresponding boronic ester (14)(15)(16)(17)(18)(19). 1 H NMR spectra were measured directly after mixing, after a few hours and, finally, after a few days.…”

“…The anomeric proton in 1 H NMR spectra was shifted to a higher field upon transformation from the respective Fmoc-Raa (2-7) to the tetrapeptide (8)(9)(10)(11)(12)(13), but receives a downfield shift again in the boronic ester (14)(15)(16)(17)(18)(19). The anomeric protons of the esterified tetrapeptides showed the strongest downfield shift in all cases.…”

“…[13] Its conceptual advantage is the self‐correcting reversibility of bond formation, if a better conformational orientation is possible, but not formed in the first place. [14a, b] The ax‐eq‐ax triol‐motif of ribopyranose, which lies in the center of our investigation, is a ligation motif expected to offer opportunities beyond the well‐established motifs like diols, thiols [15] and imines. We therefore investigate the reversibility of the esterification between a glycosylated peptide and a boronic acid or metals like Ca 2+ and propose other ligands (Figure ).…”

“…[27,30] Boronic acids have been incorporated into peptides in order to ligate diols or especially saccharides for different purposes (Figure 1e). [14]…”

Self‐assembly of peptide boroxoles on cis‐dihydroxylated oligoamide templates in water

“…The circular dichroism spectroscopic properties of the neurotoxic synthetic oligomers that are recognized and bound by human Aβ autoantibodies differed significantly from the circular dichroism spectra of the nontoxic nonproductively linked oligomers. Yet the synthesis of higher oligomers becomes exceedingly laborious, and we consequently changed gears to the reversible process of dynamic covalent chemistry (Figure ) .…”