Urea-Modified Self-Assembling Peptide Amphiphiles That Form Well-Defined Nanostructures and Hydrogels for Biomedical Applications

Abstract

Hydrogen bonding plays a critical role in the self-assembly of peptide amphiphiles (PAs). Herein, we studied the effect of replacing the amide linkage between the peptide and lipid portions of the PA with a urea group, which possesses an additional hydrogen bond donor. We prepared three PAs with the peptide sequence Phe-Phe-Glu-Glu (FFEE): two are amide-linked with hydrophobic tails of different lengths and the other possesses an alkylated urea group. The differences in the self-assembled structures formed by these PAs were assessed using diverse microscopies, nuclear magnetic resonance (NMR), and dichroism techniques. We found that the urea group influences the morphology and internal arrangement of the assemblies. Molecular dynamics simulations suggest that there are about 50% more hydrogen bonds in nanostructures assembled from the urea-PA than those assembled from the other PAs. Furthermore, in silico studies suggest the presence of urea−π stacking interactions with the phenyl group of Phe, which results in distinct peptide conformations in comparison to the amide-linked PAs. We then studied the effect of the urea modification on the mechanical properties of PA hydrogels. We found that the hydrogel made of the urea-PA exhibits increased stability and self-healing ability. In addition, it allows cell adhesion, spreading, and growth as a matrix. This study reveals that the inclusion of urea bonds might be useful in controlling the morphology, mechanical, and biological properties of self-assembled nanostructures and hydrogels formed by the PAs.

Solvent-controlled self-assembly of Fmoc protected aliphatic amino acids

“…Self-assembling materials can find diverse applications from antimicrobial materials 1,2 to emulsifiers for food, cosmetic, and biomedical industries. 3,4 Given the inherent biological interactions within these application areas, a wide variety of small biomimetic assembling molecules are the focus of this research, including peptides and peptide amphiphiles, [5][6][7] heterochiral peptides, 8,9 peptoids, 10,11 and single amino acids (SAAs). The assembly of SAAs is of particular interest for many reasons, including their ease of synthesis, 12 functional diversity, 13 stability, 14 and biocompatibility.…”

A Light Scattering Investigation of Enzymatic Gelation in Self-Assembling Peptides

“…The methodology we used in this work, can be extended to other base-triggered molecular gelators [ 19 , 20 ]. Understanding the possible effect of the urea–urease reaction in the self-assembly of urea-based SAPs [ 25 ], is particularly tempting. The fact that the gel we produced can be easily seeded with nanoparticles, is promising for possible application in drug delivery and tissue regeneration [ 8 , 64 , 65 ].…”

“…In recent years, self-assembling peptides (SAPs) have been commonly used as gelators, because they form nanofibrous matrices that resemble the fibrillar matrix of the natural ECM [ 16 ]. In order to trigger the self-assembly, an external stimulus is usually needed [ 4 , 17 ], such as adding a co-solvent [ 18 , 19 , 20 , 21 ], irradiating the sample with UV light [ 22 , 23 ], varying the temperature [ 24 , 25 ], or changing the ionic strength [ 26 ] or the pH of the system [ 27 , 28 , 29 , 30 , 31 ].…”

Research progress of self-assembling peptide hydrogels in repairing cartilage defects

“…And the incremental density of hydrogen bonding in peptides can strengthen the stiffness of nanofibers (Godbe et al, 2021). Among noncovalent interactions of biomolecules, hydrogen bonding is probably the most critical link in peptide self-assembly (Xing et al, 2022).…”