Armand Lattes

Synthetic soluble analogs of galactosylceramide (GalCer) bind to the V3 domain of HIV-1 gp120 and inhibit HIV-1-induced fusion and entry.

Galactosylceramide (GalCer) is an alternative receptor allowing human immunodeficiency virus (HIV)-1 entry into CD4-negative cells of neural and colonic origin. Several lines of evidence suggest that this glycosphingolipid recognizes the V3 region of HIV-1 surface envelope glycoprotein gp120. Since the V3 loop plays a key role in the fusion process driven by HIV-1, we decided to synthesize soluble analogs of GalCer with the aim to develop a new class of anti-HIV-1 agents that could neutralize HIV-1 infection through masking of the V3 loop. We describe a short route, in three steps, for the synthesis of soluble analogs of GalCer, using unprotected lactose as the starting sugar. The analogs were prescreened in an assay based on the interaction between a V3 loop-derived synthetic peptide and [3H]suramin, a polysulfonyl compound displaying high affinity for the V3 loop. One of the soluble analogs, i.e. CA52(n15), strongly inhibited the binding of [3H]suramin to the V3 peptide, with an IC50 of 1.2 μM. This molecule was also able to inhibit [3H]suramin binding to recombinant gp120 with similar activity. Using a competition enzyme-linked immunosorbent assay with highly specific anti-gp120 monoclonal antibodies, the region recognized by CA52(n15) could be mapped to amino acids 318-323, which corresponds to the highly conserved consensus motif GPGRAF. Interestingly, the region recognized by suramin, i.e. IQRGP-R-F, was partially overlapping this motif. CA52(n15) was able to inhibit HIV-1-induced cell fusion as well as HIV-1 entry into both CD4+ and CD4−/GalCer+ cells. A structure-activity relationship study showed that: (i) the antiviral activity of soluble analogs of GalCer correlates with V3 loop binding, and (ii) the hydrophobic moiety of the molecule plays an important role in this activity. Taken together, these data show that synthetic analogs of GalCer can inhibit HIV-1 entry into both CD4− and CD4+ cells through masking of the V3 loop.

From unsymmetrical bolaamphiphiles to supermolecules

This paper describes the synthesis and self-assembly properties of bolaamphiphiles with two different head groups: a urocanic moiety and another group such as an active function (hydroxyl, carboxylic acid or methyl ester) or a sugar (arbutin). The morphologies of the aggregates formed by these amphiphiles in aqueous solutions were studied by light scattering and transmission electron microscopy and found to be strongly dependent on three parameters (pH, structure of the amphiphile and position of the connecting links on the imidazole moiety). These investigations reveal that the form of the aggregates is mainly affected by the presence and the number of hydrogen-bonding functions in the amphiphilic structure (from vesicles to flexible fibers then rigid fibers).

Selective N-alkylation of (E)-urocanic acid

Various methods of selective alkylation of the N(τ)- and N(π)-nitrogen atoms of (E)-urocanic acid derivatives are reported. Solid-liquid phase transfer catalysis gave the best results for N(τ)-alkylation of urocanic acid alkyl esters. Liquid-liquid phase transfer catalysis allowed direct N(τ)-alkylation of urocanic acid itself. The N(π)-nitrogen atom was alkylated after protection of the N(τ)-nitrogen with a phenacyl group

Correlation between structure, aggregation behaviour and cellular toxicity of anti-HIV catanionic analogues of galactosylceramide

The self-association process of catanionic analogues of galactosylceramide and in particular the arrangement of their hydrophobic part seems to play a key role in their cellular toxicity

Use of pyrocarbonates for chemical modification of histidine residues of horseradish peroxidase

Abstract In an attempt to alter the catalytic properties of horseradish peroxidase (HRP, EC 1.11.1.7), various electrophiles were employed to modify histidine residues in this enzyme. Pyrocarbonates were found to be particularly effective, and their chromatic effect was exploited to determine the number of modified histidine residues directly by uv spectroscopy. We also developed a method for assay of histidines using diethyl pyrocarbonate, which could be extended to determination of these residues in other proteins. We showed that the catalytic activity of HRP was not affected by modification of histine residues, especially His 170, by small-sized substituents not containing reactive groups. On the other hand, electron-rich substituents, especially those with a heteroatom such as sulfur, disrupt the heme structure without producing the catalytic properties of cytochrome P450.

Characterization of recognition sites for diethyl 4-nitrobenzylphosphonate, an organophosphate pesticide analogue

In a first step towards chemical sensors using molecular imprinted materials, the complexing characteristics of diethyl 4-nitrobenzylphosphonate, an organophosphate pesticide analogue, have been studied. Two molecules have been assessed as potential interacting moieties, specifically a fluoroalcohol and an aromatic acid. The interactions have been first characterized by regular methods, such as 1H, 31P NMR and IR spectroscopy. These showed a stoichiometry 1/1 for both complexes and association constants, respectively, close to 40+/-10 and 12+/-2 M(-1). In a second step, isothermal titration calorimetry was used and a method was developed to obtain low-association constants. The association constant could be obtained for the fluoroalcohol ligand and was found equal to 63+/-0.7 M(-1). For the acidic molecule, an appropriate model could not be found, preventing the evaluation of this constant.

Liquid Crystalline Networks: Potential uses in Molecular Imprinting Technique

A novel approach to the synthesis of molecularly imprinted polymers via covalent or non-covalent linkages was studied. It relies on the use of thermotropic side-chain liquid-crystal polymer networks. The polysiloxane networks obtained after extraction of the template preserved the mesomorphic organisation set up in the presence of the guest molecule. Batch rebinding analysis were performed: this study revealed that the imprinted polymer has a much greater affinity for the template molecule than the unimprinted one, and a significant selectivity.

Effect of linking allyl and aromatic chains to histidine 170 in horseradish peroxidase.

Histidine residues in horseradish peroxidase (HRP) were modified chemically with diethyl pyrocarbonate, 4,omega-dibromoacetophenone or diallylpyrocarbonate. Histidines were chosen as His-170, the fifth ligand of the heme iron atom, forms part of the active site of this enzyme. Good yields of hemoprotein were obtained in all cases. Analysis by HPLC of peptides obtained after tryptic digestion showed that His-170 of HRP was in fact modified. The specific activity remained satisfactory after chemical modification of the histidine residues, and so the active site of HRP can thus be altered without a dramatic loss of hemoprotein or peroxidase activity. This may open routes to the preparation of novel biocatalysts.

Synthesis of Fluorinated Epoxides Opening the Way to New Hybrid Fluorocarbon-Hydrocarbon Surfactants

Abstract Two methods of epoxidation were investigated on a hybrid fluorocarbon-hydrocarbon olefin: RuCl3/bipyridine/NaIO4 and oxone/acetone. The best yield was obtained using the first method which was extended to the synthesis of new aromatic fluorinated epoxides with very good yields.

Relations entre la structure et le comportement chromatographique d'acides polyfonctionnels : Constantes de groupe et corrélations RM-pKa

Abstract Relations between the structure and the chromatographic behaviour of polyfunctional acids: group constants and correlations “ R M -p K a ” Numerous R F determinations by paper chromatography show a partition of the chromatographic map in places where substances with similar structural characteristics are localized.