Structure–Activity Relationship Study of Collagen-Derived Anti-Angiogenic Biomimetic Peptides

Structure–activity relationship (SAR) studies are essential in the generation of peptides with enhanced activity and efficacy as therapeutic agents. In this study, we report a Structure–activity relationship study for a family of mimetic peptides derived from type IV collagen with potent anti-angiogenic properties. The Structure–activity relationship study was conducted using a number of validated in vitro assays including cell proliferation, adhesion, migration, and tubule formation. We report a critical sequence (NINNV) within this peptide series, which is required for the potent anti-angiogenic activity. Detailed amino acid substitutions resulted in peptides with superior efficacy. Specifically, substitutions with isoleucine at positions 12 and 18 along with the substitution of the methionine at position 10 with the non-natural amino acid d-alanine led to an increase in potency by two orders of magnitude over the parent peptide. Several mimetic peptides in this series exhibit a significant improvement of activity over the parent peptide. This improved in vitro activity is expected to correlate with an increase in in vivo activity leading to effective peptides for anti-angiogenic therapy for different disease applications including cancer and age-related macular degeneration.