Structure-activity relationships of Bak derived peptides: affinity and specificity modulations by amino acid replacement.

To study the structure-activity relationships (SAR) and the binding activity of pro-apoptotic Bak BH3 domain, we synthesised several 16mer peptide analogues corresponding to the region (72)-GQVGRQLAIIGDDINR-(87). Using different amino acids varying in length, steric and electronic properties, we investigated the role and the nature of physicochemical parameters of residues Val74, Leu78, Ile81 and Ile85, previously identified to be crucial for interactions. With this aim, we measured the affinity of these peptides on two anti-apoptotic proteins Bcl-x(L) and Bcl-2 by a polarization fluorescence competitive assay. We defined that the most potent peptide on Bcl-x(L), which presents a 4.6-fold increase as compared to the parent peptide affinity, was obtained when Ile85 was mutated with a 4-chlorophenylalanine. Finally, assays of eight Bak peptide analogues on Bcl-2 allowed us to postulate that modulations at position 78 could afford peptides with a binding selectivity enhanced for Bcl-x(L). These pharmacological and physicochemical parameter data should prove useful for the rational design of non-peptide ligands as potential antagonists of Bcl-2 protein interactions.

[Optimizing French scientific and economic performance: the Cifre system of public-private partnership in doctoral research and Servier's contribution]. / Formation à la recherche et partenariats de recherche public-privé: contribuer ensemble à l'excellence scientifique et à la croissance économique.

The European Union has set itself the daunting target of becoming the world's most competitive and dynamic knowledge-based economy by 2010. Any hope of success against the United States and the Asian tiger economies lies in the quality of scientific and technological research. In France, postgraduate training has long labored under a deep academia/industry divide. Although the universities have introduced supervised 3 year doctoral courses along the lines of the English-speaking countries, they still produce too many postdocs with little experience or understanding of, and little taste for, the private sector. This ignores career realities: the public sector can offer employment to only half the postdocs it produces. The rest must fall back on positions in the private sector, in some cases with a sense of failure, ill suiting them to drive the intellectual economy forwards compared to their international competitors. To combat the divide and emphasize the quality of the research training available within industry, the public/private National Association for Technical Research (ANRT), acting on behalf of the Ministry of Research, created the Industrial Research Training Agreement (Cifre) scheme in 1981. Higher education laboratories and private companies combine to offer doctoral students the opportunity to undertake their 3 year course in a mixed public/private environment (the exact ratio is not defined but in the case of the Servier Research Group, an early and active participant in the scheme, at least one third of the course is spent in the private sector). The doctoral thesis is thereby transformed into a meaningful career qualification. Funded by the Ministry, with maintenance grants to the students and compensatory payments to the companies, the Cifre scheme, which is currently being expanded, has produced 12,000 postdocs personally and intellectually equipped for careers transiting seamlessly between the public and private sectors, to the enrichment of each.

S 23521 decreases food intake and body weight gain in diet-induced obese rats.

OBJECTIVE: To investigate the effect of S 23521, a new glucagon-like peptide-1-(7-36) amide analogue, on food intake and body weight gain in obese rats, as well as on gene expression of several proteins involved in energy homeostasis. RESEARCH METHODS AND PROCEDURES: Lean and diet-induced obese rats were treated with either S 23521 or vehicle. S 23521 was given either intraperitoneally (10 or 100 microg/kg) or subcutaneously (100 microg/kg) for 14 and 20 days, respectively. Because the low-dose treatment did not affect food intake and body weight, the subcutaneous treatment at high dose was selected to test the effect on selected end-points. RESULTS: Treated obese rats significantly decreased their cumulative energy intake in relation to vehicle-treated counterparts (3401 +/- 65 vs. 3898 +/- 72 kcal/kg per 20 days; p < 0.05). Moreover, their body weight gain was reduced by 110%, adiposity was reduced by 20%, and plasma triglyceride levels were reduced by 38%. The treatment also improved glucose tolerance and insulin sensitivity of obese rats. Regarding gene expression, no changes in uncoupling protein-1, uncoupling protein-3, leptin, resistin, and peroxisome proliferator-activated receptor (PPAR)-gamma were observed. DISCUSSION: S 23521 is an effective glucagon-like peptide-1-(7-36) amide analogue, which induced a decrease in energy intake, body weight, and adiposity in a rat model of diet-induced obesity. In addition, the treatment also improved glucose tolerance and insulin sensitivity of obese rats. These results strongly support S 23521 as a putative molecule for the treatment of obesity.

Structural requirements of the N-terminal region of GLP-1-[7-37]-NH2 for receptor interaction and cAMP production.

A series of GLP-1-[7-36]-NH(2) (tGLP-1) and GLP-1-[7-37] analogs modified in position 7, 8, 9 and 36, have been designed and evaluated on murine GLP-1 receptors expressed in RIN T3 cells for both their affinity and activity. Ten of the synthesized peptides were found full agonists with activities superior or at least equal to that of the native hormone. Five of them were investigated for their plasmatic stability and the most stable, [a(8)-desR(36)]GLP-1-[7-37]- NH(2) (Compound 8), evaluated in vivo in a glucose tolerance test which confirmed a clearly longer activity than that of the native hormone. We also performed circular dichroism study and propose a hypothetical structural model explaining the most part of observed activities of GLP-1 analogs on RIN T3 cells.