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 M_NH2 {Fmoc-FFβAR(K)βA-NH₂ consisting of an RGD mimic, [R(K)], with an amide terminus}, M_OH {Fmoc-FFβAR(K)βA-OH consisting of an RGD mimic, [R(K)], with acid terminus}, and M_R (Fmoc-FFβARGDβA-NH₂ consisting of an RGD peptide, reference) with multifunctional activity. Here, we reported the synthesis, characterization, and performance of a reversed derivative, R-M_NH2 (Fmoc-FFβA(K)RβA-NH₂ consisting of an RGD mimic, [K(R)], with an amide terminus) of an antimicrobial cell adhesive peptide, M_NH2. Both peptides (M_NH2 and R-M_NH2) were found to interact with αvβ3 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 (M_R, R-M_NH2, M_NH2, and M_OH) 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, M_NH2, and its reversed derivative, R-M_NH2, showed antimicrobial activity in both in vitro and in vivo studies. Of these, M_NH2 showed the highest integrin-mediated spreading, migration, and proliferation of dermal cells in vitro as well as in vivo. Therefore, the M_NH2 peptide mimic represents a paradigm shift in the development of dermoconductive strategies to treat chronic wounds.