Exploring the space of histidine containing dipeptides in search of novel efficient RCS sequestering agents

• Many proteinogenic His-containing dipeptides show remarkable HNE quenching activity.
• Diastereoisomeric peptides reveal the role of configuration on activity and selectivity.
• Activity data are amenable to QSAR analyses thus revealing key factors in quenching.
• l-Lys-l-His-OMe and l-Tyr-d-His-OMe appear to be the most promising dipeptides.

The study reports a set of forty proteinogenic histidine-containing dipeptides as potential carbonyl quenchers. The peptides were chosen to cover as exhaustively as possible the accessible chemical space, and their quenching activities toward 4-hydroxy-2-nonenal (HNE) and pyridoxal were evaluated by HPLC analyses. The peptides were capped at the C-terminus as methyl esters or amides to favor their resistance to proteolysis and diastereoisomeric pairs were considered to reveal the influence of configuration on quenching. On average, the examined dipeptides are less active than the parent compound carnosine (βAla + His) thus emphasizing the unfavorable effect of the shortening of the βAla residue as confirmed by the control dipeptide Gly-His. Nevertheless, some peptides show promising activities toward HNE combined with a remarkable selectivity. The results emphasize the beneficial role of aromatic and positively charged residues, while negatively charged and H-bonding side chains show a detrimental effect on quenching. As a trend, ester derivatives are slightly more active than amides while heterochiral peptides are more active than their homochiral diastereoisomer. Overall, the results reveal that quenching activity strongly depends on conformational effects and vicinal residues (as evidenced by the reported QSAR analysis), offering insightful clues for the design of improved carbonyl quenchers and to rationalize the specific reactivity of histidine residues within proteins.

The HNE versus pyridoxal quenching plot can be subdivided into four fuzzy regions defined by activity averages. Among active and selective dipeptides, l-Lys-l-His-OMe and l-Tyr-d-His-OMe appear to be the most promising ones.Figure optionsDownload as PowerPoint slide