CONTEXT

AGE are a heterogeneous group of molecules formed within the body during aging and, at an accelerated rate, in diabetes. AGE result from the non-enzymatic reaction of proteins, lipids, and nucleic acids with reducing sugars such as glucose but mainly with compounds containing reactive carbonyl groups [the most reactive a-dicarbonyls are glyoxal (GO) and methylglyoxal (MG)]. The AGE deteriorate the structure and impairs the biological function of the implicated biomolecules leading consequently to the cellular damages. In vivo and in vitro studies show that AGE affect also cellular signalling and gene expression. The generation of AGE contributes mainly to diabetes related complications and chronological aging. In view of deleterious consequences of AGE formation, numerous agents preventing AGE accumulation were investigated. Therapeutic interventions for reducing AGE might target their formation by decreasing the level of a-dicarbonyls.

TECHNICAL DESCRIPTION

This invention describes the synthesis and the biolgical activites of new class of N-terminal diaminopropionic acid (Dap) peptides. These molecules were identified as the highly reactive scavengers of a-dicarbonyl compounds. They inhibit in vitro glycation process induced by methylglyoxal (MG) of a number of proteins (insuline, glyoxalase I, actine, tubuline, lysozyme, SOD, RNase, somatostatine). The in vitro expositions of all studied proteins to MG in the presence of N-terminal Dap peptides allow preserving their structure and biological activity. Moreover, these peptides protect endothelial cells and human keratinocytes against cytotoxicity induced by MG. The results of ex vivo studies realized on the explants of human skin treated with MG show that N-terminal Dap peptides totally inhibit the formation of AGE (N^e-carboxymethyl-lysin (CML) and pentosidin) induced by MG. Furthermore, topical treatment of ex vivo cultured skin explants with one of N-terminal Dap peptides increases the thickness of the epidermis and upregulates the synthesis of collagen I and III as well as the glycoaminoglycans (GAGs). Mutagenic activities of tested peptides and their metabolites according to the Ames assay are negative.

INDUSTRIAL APPLICATIONS

Cosmetic use of N-terminal Dap peptides as anti-aging agents.
Pharmaceutical use of N-terminal Dap peptides to treat the diseases as well as the deleterious effects due to the formation of AGE.

DEVELOPMENT STAGE

The experimental approches  used :
Structural modifications : RP-HPLC analysis, SDS/PAGE electrophoresis
Biological activities : ELISA, studies of enzymatic activity, studies of peptides stability (pH 3.5-6.5), cell culture of endothelial cells (EA.hy926) and human keratinocytes, ex vivo human skin explants assay, histology and immune-histochemistry.
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