Expanding the Functional Scope of the Fmoc-Diphenylalanine Hydrogelator by Introducing a Rigidifying and Chemically Active Urea Backbone Modification

Peptidomimetic low-molecular-weight hydrogelators, a class of peptide-like molecules with various backbone amide modifications, typically give rise to hydrogels of diverse properties and increased stability compared to peptide hydrogelators. Here, a new peptidomimetic low-molecular-weight hydrogelator is designed based on the well-studied N-fluorenylmethoxycarbonyl diphenylalanine (Fmoc-FF) peptide by replacing the amide bond with a frequently employed amide bond surrogate, the urea moiety, aiming to increase hydrogen bonding capabilities. This designed ureidopeptide, termed FmocPheNHCONHPheOH (Fmoc-FuF), forms hydrogels with improved mechanical properties, as compared to those formed by the unmodified Fmoc-FF. A combination of experimental and computational structural methods shows that hydrogen bonding and aromatic interactions facilitate Fmoc-FuF gel formation. The Fmoc-FuF hydrogel possesses properties favorable for biomedical applications, including shear thinning, self-healing, and in vitro cellular biocompatibility. Additionally, the Fmoc-FuF, but not Fmoc-FF, hydrogel presents a range of functionalities useful for other applications, including antifouling, slow release of urea encapsulated in the gel at a high concentration, selective mechanical response to fluoride anions, and reduction of metal ions into catalytic nanoparticles. This study demonstrates how a simple backbone modification can enhance the mechanical properties and functional scope of a peptide hydrogel.