Collagen-inspired biomimetic peptides as therapeutic agents against methylglyoxal-mediated damage

Damage from increased levels of advanced glycation end-products (AGEs) is linked to aging and health problems such as diabetes, neurological disorders, and cardiovascular disease. Methylglyoxal (MG), a primary AGE precursor, is metabolized under normal conditions by the enzyme glyoxalase-1 (Glo1). However, in aging and disease, conditions including hypoxia, inflammation, ischemia, and oxidative stress increase MG production while limiting Glo1 activity, leading to AGE accumulation. This suggests that MG may be a therapeutic target for limiting the damage caused by AGEs. In this work, short collagen-based peptide sequences with varying numbers and positions of the amino acid arginine (a target for MG) are generated, characterized, and tested for their ability to trap MG. The peptide with 3 arginine residues on the C-terminal forms the most stable triple helix structure and exhibits the best MG-trapping capacity. Endothelial cells cultured in the presence of MG and treated with the best peptide candidate have superior viability, express less RAGE (receptor for AGEs), and have decreased intracellular AGE accumulation compared to untreated cells. This peptide may be a promising therapeutic approach to trap MG and limit its negative effects on aging and disease.