Exploring Fmoc-Phe-OH self-assembly for the development of functional soft biomaterials

Abstract

The design and development of self-assembling materials derived from amino acids and short peptides have gained growing significance in functional soft biomaterials. Attaching aromatic functional groups to these molecules enhances their self-assembly and gelation capabilities. Among these, 9-fluorenylmethoxy carbonyl (Fmoc), commonly used for N-terminal protection of amino acids, has been extensively studied over the past two decades. These aromatic groups primarily promote self-assembly through aromatic–aromatic interactions, supported by other non-covalent interactions present in the peptide structures. Approximately 16 years ago, the Fmoc derivative of phenylalanine (Fmoc-Phe-OH) was first reported to form a supramolecular hydrogel. Since then, extensive research has been carried out on the gelation behavior of Fmoc-Phe-OH and its related compounds. This review systematically shed lights on the conditions under which Fmoc-Phe-OH and its derivatives undergo gelation, including buffer systems, pH adjustment, and solvent-switching techniques. Further discussion is provided on how modifications, such as ring substitutions on the phenyl ring and alterations at the C-terminal of phenylalanine, affect self-assembly and gelation. Co-assembly with various small molecules has also been shown to enhance the mechanical properties and additional functionality of the resulting biomaterials. Finally, the review highlights diverse applications of these materials, including their use in drug delivery, antimicrobial formulations, nanomaterial scaffolds, and hybrid gels with tunable properties. We hope this work will be beneficial in understanding the molecular engineering approach in advancing amino-acid-based functional materials in different research areas of supramolecular chemistry.