title: Exploring the space of histidine containing dipeptides in search of novel efficient RCS sequestering agents.
abstract: 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.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli, 25, I-20133 Milano, Italy. Giulio.Vistoli@unimi.it
authors.forename: Giulio
authors.initials: G
authors.lastname: Vistoli
authors.forename: Danilo
authors.initials: D
authors.lastname: De Maddis
authors.forename: Valentina
authors.initials: V
authors.lastname: Straniero
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pedretti
authors.forename: Marco
authors.initials: M
authors.lastname: Pallavicini
authors.forename: Ermanno
authors.initials: E
authors.lastname: Valoti
authors.forename: Marina
authors.initials: M
authors.lastname: Carini
authors.forename: Bernard
authors.initials: B
authors.lastname: Testa
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Aldini
mesh_terms: D000328:Adult; D000447:Aldehydes / Q000378:metabolism*; D002336:Carnosine / Q000737:chemistry; D004151:Dipeptides / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology*; D006639:Histidine; D006801:Humans; D008958:Models, Molecular; D055550:Protein Stability; D059748:Proteolysis / Q000187:drug effects; D011730:Pyridoxal / Q000378:metabolism
chemical_list: D000447:Aldehydes; D004151:Dipeptides; D011730:Pyridoxal; D006639:Histidine; D002336:Carnosine; C027576:4-hydroxy-2-nonenal
keywords: 4-Hydroxy-2-nonenal; Carbonyl scavengers; Carnosine; Diastereoisomeric dipeptides; Histidine nucleophilicity; Reactive carbonyl species