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

We develop templates that can be used to stabilize consistent oligomers of a bioactive peptide. In the present study, we synthesize oligomers of an antibody epitope from the amyloidogenic prion protein. Dynamic covalent chemistry is the basis for the spontaneous condensation of 2, 3, 4 or 6 peptides with qualified polyol templates presenting the required number of bioorthogonal ligation sites. To study this process in aqueous solution, the N-terminal amino acid of a 13-mer peptide is first acylated with 4-carboxy-benzoboroxole (1-hydroxy-1,3-dihydrobenzo[c][1,2] oxaborole-5-carboxylic acid) and then mixed with the template to obtain self-assembled miniamyloids of specified degree of oligomerization. The template is assembled from bicyclic dipeptides of alternating d- and l-stereochemistry. The cis-diol group of this dipeptide hot=Tap (hot: d-hydroxythreonine, Tap: l-thiaproline) has sufficiently high affinity for boroxoles in water. A single N -hot=Tap-OMe dipeptide template forms a 1 : 1 complex with 4-carboxy-benzoboroxole with excellent diastereoselectivity. The oligomeric template N -(hot=Tap) -OMe (n = 2, 3, 4 or 6) presents a regular pattern of 2, 3, 4 or 6 cis-diol groups for the spontaneous esterification with the same number of boronic acids. Nuclear magnetic resonance identifies the homogenous regioselectivity and stereoselectivity of this ligation process. The combination of electron-poor benzoboroxoles with this optimized cis-diol template allows for the complete ligation under high-dilution conditions in water with only 1.3 equivalents of peptide-boroxole per diol functionality. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.