The carbonyl scavenger carnosine ameliorates dyslipidaemia and renal function in Zucker obese rats.

The metabolic syndrome is a risk factor that increases the risk for development of renal and vascular complications. This study addresses the effects of chronic administration of the endogenous dipeptide carnosine (ß-alanyl-L-histidine, L-CAR) and of its enantiomer (ß-alanyl-D-histidine, D-CAR) on hyperlipidaemia, hypertension, advanced glycation end products, advanced lipoxidation end products formation and development of nephropathy in the non-diabetic, Zucker obese rat. The Zucker rats received a daily dose of L-CAR or D-CAR (30 mg/kg in drinking water) for 24 weeks. Systolic blood pressure was recorded monthly. At the end of the treatment, plasma levels of triglycerides, total cholesterol, glucose, insulin, creatinine and urinary levels of total protein, albumin and creatinine were measured. Several indices of oxidative/carbonyl stress were also measured in plasma, urine and renal tissue. We found that both L- and D-CAR greatly reduced obese-related diseases in obese Zucker rat, by significantly restraining the development of dyslipidaemia, hypertension and renal injury, as demonstrated by both urinary parameters and electron microscopy examinations of renal tissue. Because the protective effect elicited by L- and D-CAR was almost superimposable, we conclude that the pharmacological action of L-CAR is not due to a pro-histaminic effect (D-CAR is not a precursor of histidine, since it is stable to peptidic hydrolysis), and prompted us to propose that some of the biological effects can be mediated by a direct carbonyl quenching mechanism.

Design, synthesis, and evaluation of carnosine derivatives as selective and efficient sequestering agents of cytotoxic reactive carbonyl species.

Carnosine aryl derivatives as sequestering agents of RCS: Reactive carbonyl species (RCS) are cytotoxic mediators representing a novel drug target, as they are presumed to play a pathogenic role in several diseases. Carnosine is a selective RCS-sequestering agent, but is rapidly hydrolyzed by serum carnosinase. Herein we describe the in silico design, synthesis, and evaluation of a set of carnosine aryl derivatives.Reactive carbonyl species (RCS) are important cytotoxic mediators generated by lipid oxidation of polyunsaturated fatty acids (PUFAs) and represent a novel drug target, as they are presumed to play a pathogenic role in several diseases. L-Carnosine (L-CAR, beta-alanyl-L-histidine) is a specific detoxifying agent of RCS, but is rapidly hydrolyzed in human serum by carnosinase, a specific dipeptidase. Herein we describe the in silico design, synthesis, and biological evaluation of carnosine derivatives that are resistant to carnosinase and that have increased quenching efficacy. Stability against carnosinase-mediated turnover was achieved by isomerization of the histidine residue, leading to D-carnosine (D-CAR, beta-alanyl-D-histidine), which maintains the same quenching activity of L-carnosine. A molecular modeling approach was then used to design derivatives characterized by an increased quenching efficacy. The most promising candidates were synthesized, and their stability and quenching activity were evaluated. This study describes a set of aryl derivatives that are characterized by high stability in human plasma and a quenching activity toward 4-hydroxy-trans-2-nonenal (HNE), chosen as a model of RCS, up to threefold greater than D-carnosine.

Modeling of the intestinal peptide transporter hPepT1 and analysis of its transport capacities by docking and pharmacophore mapping.

An early pharmacokinetic screen for peptidomimetic drugs should have the ability to predict molecules with high affinity for intestinal transporters, as peptide-like derivatives are seldom absorbed passively. Hence, the first objective of this study was to generate a reliable model for the structure of the hPepT1 protein, which is the main intestinal transporter involved in the absorption of both dietary peptides and peptidomimetics. The modeling was based on the resolved structure of the homologous bacterial lactose permease LacY using a fragmental strategy. The interaction capacities of the hPepT1 model were explored by docking a set of 50 known ligands. Despite the known predilection of hPepT1 for hydrophobic ligands, docking results unveiled the key role of the polar interactions stabilized by charged termini, especially concerning the ammonium head group. The docking results were further verified by developing a pharmacophore model that confirmed the key features required for optimal hPepT1 affinity. The consistency of the docking results and the agreement with the pharmacophore model afford an encouraging validation for the proposed model and suggest that it can be exploited to design peptide-like molecules with an improved affinity for such a transporter.