Short peptides containing Norbornene amino acid (NRB): role of the NRB scaffold in self-assembly

A number of papers report on spontaneous assembly of peptides into ordered nanostructures with a variety of morphologies and this number is still expanding.[1] Besides the numerous advantages of using peptides as building blocks for different types of nanostructures, some limitations are well-known such as a low stability in biological medium and their unstable conformation especially when they are short or medium-sized. The insertion of unnatural amino acids in the peptide sequences is a well-known tool to overcome these problems. Both theoretical and experimental studies on this subject have been published and, in particular, the group of Cα,-tetrasubstituted residues, in which the quaternary α-carbon is part of a ring has been the object of extensive investigation.[2] Notwithstanding this interest, studies on the self-assembly of short peptides containing cyclic Cα-tetrasubstituted amino acids are very rare.[3] The two diastereoisomeric pentapeptides AcAla-NRB-Ala-Aib-AlaNH2 1 and 2, containing the two enantiomers of the non-proteinogenic Cα-tetrasubstituted norbornene amino acid (NRB), were synthesized and their conformational analysis was performed. Interestingly, despite they are made of hydrophobic amino acids, they resulted insoluble in organic solvent, but completely soluble in water. The formation of supramolecular assemblies in water was assessed by TEM and DLS. Moreover, the stability of the aggregates in fetal bovine serum was evaluated and tested by DLS. A comparison between NRB containing peptides and other peptides containing cyclic and non-cyclic Cα-tetrasubstituted residues (i.e. Aib, Ac5AA) was done in order to better understand the role played by the NRB residue in aggregation phenomena.