Formation and Modulation of Nanotubular Assemblies of Oligourea Foldamers in Aqueous Conditions using Alcohol Additives.

There is considerable interest in the rational design of controllable, bioinspired supramolecular systems as a potential means to create new biocompatible and functional materials able to mimic and build upon the characteristics of natural biopolymers. Here, the alcohol-controlled aqueous self-assembly of an amphiphilic helical oligourea foldamer (artificial folded oligomer) into a diverse array of tubular fibril architectures is reported. Electron microscopy studies provide details of the morphological evolution of the foldamer nanostructures from protofibrils to fibers, with high resolution X-ray crystal structures providing an atomic-scale view of these assemblies, and solution studies indicating the assembly and morphology to be affected by alcohol polarity and concentration. Overall, the results reported here highlight oligourea foldamers as suitable building blocks for the formation of a diverse range of tubular morphologies in a controllable manner.

Peptide-oligourea hybrids analogue of GLP-1 with improved action in vivo.

Peptides have gained so much attention in the last decade that they are now part of the main strategies, with small molecules and biologics, for developing new medicines. Despite substantial progress, the successful development of peptides as drugs still requires a number of limitations to be addressed, including short in vivo half-lives and poor membrane permeability. Here, we describe the use of oligourea foldamers as tool to improve the pharmaceutical properties of GLP-1, a 31 amino acid peptide hormone involved in metabolism and glycemic control. Our strategy consists in replacing four consecutive amino acids of GLP-1 by three consecutive ureido residues by capitalizing on the structural resemblance of oligourea and α-peptide helices. The efficacy of the approach is demonstrated with three GLP-1-oligourea hybrids showing prolonged activity in vivo. Our findings should enable the use of oligoureas in other peptides to improve their pharmaceutical properties and may provide new therapeutic applications.

Ureidopeptide GLP-1 analogues with prolonged activity in vivo via signal bias and altered receptor trafficking.

The high demand of the pharmaceutical industry for new modalities to address the diversification of biological targets with large surfaces of interaction led us to investigate the replacement of α-amino acid residues with ureido units at selected positions in peptides to improve potency and generate effective incretin mimics. Based on molecular dynamics simulations, N-terminally modified GLP-1 analogues with a ureido residue replacement at position 2 were synthesized and showed preservation of agonist activity while exhibiting a substantial increase in stability. This enabling platform was applied to exenatide and lixisenatide analogues to generate two new ureidopeptides with antidiabetic properties and longer duration of action. Further analyses demonstrated that the improvement was due mainly to differences in signal bias and trafficking of the GLP-1 receptor. This study demonstrates the efficacy of single α-amino acid substitution with ureido residues to design long lasting peptides.

Molecular Recognition within the Cavity of a Foldamer Helix Bundle: Encapsulation of Primary Alcohols in Aqueous Conditions.

Artificial synthetic molecules able to adopt well-defined stable secondary structures comparable to those found in nature ("foldamers") have considerable potential for use in a range of applications such as biomaterials, biorecognition, nanomachines and as therapeutic agents. The development of foldamers with the ability to bind and encapsulate "guest" molecules is of particular interest; as such an ability is a key step toward the development of artificial sensors, receptors and drug-delivery vectors. Although significant progress has been reported within this context, foldamer capsules reported thus far are largely restricted to organic solvent systems, and it is likely that the move to aqueous conditions will prove challenging. Toward this end, we report here structural studies into the ability of a recently reported water-soluble self-assembled foldamer helix bundle to encapsulate simple guest molecules within an internal cavity. Seven high-resolution aqueous crystal structures are reported, accompanied by molecular dynamics and high-field NMR solution data, showing for the first time that encapsulation of guests by a complex self-assembled foldamer in aqueous conditions is possible. The findings also provide ample insight for the future functional development of this system.

Shaping quaternary assemblies of water-soluble non-peptide helical foldamers by sequence manipulation.

The design and construction of biomimetic self-assembling systems is a challenging yet potentially highly rewarding endeavour that contributes to the development of new biomaterials, catalysts, drug-delivery systems and tools for the manipulation of biological processes. Significant progress has been achieved by engineering self-assembling DNA-, protein- and peptide-based building units. However, the design of entirely new, completely non-natural folded architectures that resemble biopolymers ('foldamers') and have the ability to self-assemble into atomically precise nanostructures in aqueous conditions has proved exceptionally challenging. Here we report the modular design, formation and structural elucidation at the atomic level of a series of diverse quaternary arrangements formed by the self-assembly of short amphiphilic α-helicomimetic foldamers that bear proteinaceous side chains. We show that the final quaternary assembly can be controlled at the sequence level, which permits the programmed formation of either discrete helical bundles that contain isolated cavities or pH-responsive water-filled channels with controllable pore diameters.

α-Peptide-Oligourea Chimeras: Stabilization of Short α-Helices by Non-Peptide Helical Foldamers.

Short α-peptides with less than 10 residues generally display a low propensity to nucleate stable helical conformations. While various strategies to stabilize peptide helices have been previously reported, the ability of non-peptide helical foldamers to stabilize α-helices when fused to short α-peptide segments has not been investigated. Towards this end, structural investigations into a series of chimeric oligomers obtained by joining aliphatic oligoureas to the C- or N-termini of α-peptides are described. All chimeras were found to be fully helical, with as few as 2 (or 3) urea units sufficient to propagate an α-helical conformation in the fused peptide segment. The remarkable compatibility of α-peptides with oligoureas described here, along with the simplicity of the approach, highlights the potential of interfacing natural and non-peptide backbones as a means to further control the behavior of α-peptides.