Self-assembled Arginine-Glycine-Aspartic Acid Mimic Peptide Hydrogels as Multifunctional Biomaterials for Wound Healing

Clinical management of nonhealing ulcers requires advanced materials that can enhance wound closure rates without relying on the release of drugs or other growth factors to obviate systemic deleterious side effects. In our previous work, we synthesized an integrin-binding cell adhesive MNH2 {Fmoc-FF beta AR(K)beta A-NH2 consisting of an RGD mimic, [R(K)], with an amide terminus}, MOH {Fmoc-FF beta AR(K)beta A-OH consisting of an RGD mimic, [R(K)], with acid terminus}, and MR (Fmoc-FF beta ARGD beta A-NH2 consisting of an RGD peptide, reference) with multifunctional activity. Here, we reported the synthesis, characterization, and performance of a reversed derivative, R-MNH2 (Fmoc-FF beta A(K)R beta A-NH2 consisting of an RGD mimic, [K(R)], with an amide terminus) of an antimicrobial cell adhesive peptide, MNH2. Both peptides (MNH2 and R-MNH2) were found to interact with alpha v beta 3 integrin, as shown by docking studies; however, they differed in cell adhesive properties, hydrogel formation, and antimicrobial efficacy. Later, the wound healing ability of a series of RGD/RGD peptide mimics (MR, R-MNH2, MNH2, and MOH) was studied in a methicillin-resistant Staphylococcus aureus (MRSA)-infected Balb/c mouse model. All studied peptides showed cell adhesion and wound healing properties; however, only the amide-terminal RGD peptide mimic, MNH2, and its reversed derivative, R-MNH2, showed antimicrobial activity in both in vitro and in vivo studies. Of these, MNH2 showed the highest integrin-mediated spreading, migration, and proliferation of dermal cells in vitro as well as in vivo. Therefore, the MNH2 peptide mimic represents a paradigm shift in the development of dermoconductive strategies to treat chronic wounds.