Biomedical subjects

B Déprez

Publications and source records attributed to B Déprez.

4 recordsLinked to original sources

PubMed2001

From hit to lead. Combining two complementary methods for focused library design. Application to mu opiate ligands.

Compound 1 obtained by random screening and displaying a micromolar activity on the mu opiate receptor was chosen as a starting point for optimization. Two complementary concepts of similarity were used for the design of analogues and compared. These are based, respectively, on a computer-aided comparison of pharmacophoric patterns and on topological similarity. The structure-activity relationships are discussed in light of both similarity concepts. Compound 40, an N-methyl-3-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decyl)acetamide derivative, designed by combining the structure-activity relationships enlightened by each method, has a subnanomolar affinity for mu (h) receptor (IC(50) = 0.9 nM). It is a promising lead, allowing the design of a new series of analogues substituted at the N-3 of the spirocycle moiety.

Animals↗

PubMed2001

From hit to lead. Analyzing structure-profile relationships.

Two compounds, obtained by random screening, and displaying micromolar activities on the mu opiate receptor were used as starting points for optimization. In that work, the traditional concept of the activity of a compound (related to one or a few targets) was extended to the comprehensive pharmacological profile of that compound on more than 70 receptors, transporters, and channels relevant to a CNS-oriented project. Using the two complementary design strategies based on two similarity concepts described in the previous paper, we have obtained analogues with IC(50) values ranging between 0.9 nM and a few micromolar on the mu receptor and displaying qualitatively different profiles. We discuss here, both on a case-by-case basis and from a statistical standpoint, the pharmacological profiles in light of the two similarity concepts.

Brain↗

PubMed1995

Pimelautide or trimexautide as built-in adjuvants associated with an HIV-1-derived peptide: synthesis and in vivo induction of antibody and virus-specific cytotoxic T-lymphocyte-mediated response.

Covalent association of lipopeptidic immunostimulants is known to improve the immunogenicity of short peptides. In this paper, we describe the synthesis of four analytically pure immunogens, prepared by two different strategies, in which a hexadecameric peptide (V3) derived from the principal neutralizing domain of HIV-1 envelope glycoprotein was associated with two different murein-derived lauroyl-peptides, Pimelautide (RP 44102), or Trimexautide (RP 56142). The in vivo immunogenicity of these compounds was evaluated according to two different criteria: the ability to elicit a cellular-T cytotoxic (CTL response) and the ability to stimulate antibody response. Our studies show that one of our compounds (TrxSucV3) was able to efficiently induce a relevant virus-specific CTL response, while another one (PimSucV3) was able to stimulate a strong antibody response to the linked peptide, or to a co-injected protein. These results suggest that both activities rely on different structure-activity relationships and that such a chemically defined model of peptide vaccines may be used to selectively stimulate subpopulations of immunocompetent cells.

Adjuvants, Immunologic↗

PubMed1995

Long-lasting anti-viral cytotoxic T lymphocytes induced in vivo with chimeric-multirestricted lipopeptides.

Cytotoxic T lymphocytes (CTL) play a major role in protective immunity against viral diseases. However, the antigenic formulations that can be used in vaccinations able to generate virus-specific CTL responses in vivo have yet to be defined. We have previously shown that HIV-1-specific CTL can be elicited in mice by injecting without adjuvant a synthetic peptide of the envelope glycoprotein that has been modified by the addition of a simple lipid tail to the end of the sequence (lipopeptide). The present study set out to address the question of whether such immunogens may be appropriate for preparing a human synthetic vaccine. We first showed that CTL were effectively induced by lipopeptides when given s.c. or i.p. We evidenced that the in vivo induction required stimulation of a concomitant specific T helper cell response, implying the presence of at least one CD4 epitope in the synthetic sequence used. Bearing in mind the particular properties that would be required in a prospective human peptide vaccine, we conceived a strategy in which a virus-specific CTL response could be generated in mice of different haplotypes using a single lipopeptide. We therefore tested a lipopeptide construct that integrated a synthetic sequence having three colinear epitopes of the influenza virus nucleoprotein, each restricted to a different H-2 haplotype. We found that a CTL response could be elicited to all three epitopes of this chimeric multirestricted lipopeptide construct. Finally, we have attempted to estimate the duration of the responses; strong CTL activities were still present up to six months after the last injection. These findings indicate that this approach may be suitable for developing a synthetic vaccine for human use.

Animals↗