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Claude Didierjean

Publications and source records attributed to Claude Didierjean.

14 recordsLinked to original sources
PubMed2006

1,3,5-Triazepane-2,6-diones as structurally diverse and conformationally constrained dipeptide mimetics: identification of malaria liver stage inhibitors from a small pilot library.

The development of the 1,3,5-triazepane-2,6-dione system as a novel, conformationally restricted, and readily accessible class of dipeptidomimetics is reported. The synthesis of the densely functionalized 1,3,5-triazepane-2,6-dione skeleton was achieved in only four steps from a variety of simple linear dipeptide precursors. To extend the practical value of 1,3,5-triazepane-2,6-diones, a general polymer-assisted solution-phase synthesis approach amenable to library production in a multiparallel format was developed. The conformational preferences of the 1,3,5-triazepane-2,6-dione skeleton were investigated in detail by NMR spectroscopy and X-ray diffraction. The ring exhibits a characteristic folded conformation which was compared to that of related dipeptide-derived scaffolds including the more planar 2,5-diketopiperazine (DKP). Molecular and structural diversity was increased further through post-cyclization appending operations at urea nitrogens. Preliminary biological screens of a small collection of 1,3,5-triazepane-2,6-diones revealed inhibitors of the underexplored malaria liver stage and suggest strong potential for this dipeptide-derived scaffold to interfere with and to modulate biological pathways.

Combinatorial Chemistry Techniques↗
PubMed2006

The first crystal structure of a thioacylenzyme intermediate in the ALDH family: new coenzyme conformation and relevance to catalysis.

Crystal structures of several members of the nonphosphorylating CoA-independent aldehyde dehydrogenase (ALDH) family have shown that the peculiar binding mode of the cofactor to the Rossmann fold results in a conformational flexibility for the nicotinamide moiety of the cofactor. This has been hypothesized to constitute an essential feature of the catalytic mechanism because the conformation of the cofactor required for the acylation step is not appropriate for the deacylation step. In the present study, the structure of a reaction intermediate of the E268A-glyceraldehyde 3-phosphate dehydrogenase (GAPN) from Streptococcus mutans, obtained by soaking the crystals of the enzyme/NADP complex with the natural substrate, is reported. The substrate is bound covalently in the four monomers and presents the geometric characteristics expected for a thioacylenzyme intermediate. Control experiments assessed that reduction of the coenzyme has occurred within the crystal. The structure reveals that reduction of the cofactor upon acylation leads to an extensive motion of the nicotinamide moiety with a flip of the reduced pyridinium ring away from the active site without significant changes of the protein structure. This event positions the reduced nicotinamide moiety in a pocket that likely constitutes the exit door for NADPH. Arguments are provided that the structure reported here constitutes a reasonable picture of the first thioacylenzyme intermediate characterized thus far in the ALDH family and that the position of the reduced nicotinamide moiety observed in GAPN is the one suitable for the deacylation step within all of the nonphosphorylating CoA-independent ALDH family.

Acylation↗
PubMed2005

Structural investigation of "cis" and "trans" vinylogous peptides: cis-vinylog turn in folded cis-vinylogous peptides, an excellent mimic of the natural beta-turn.

[structure: see text] Various sequences of modified peptides including those containing a cis- or trans-vinylogous residue have been studied using X-ray diffraction in the solid state and 1H NMR and IR spectroscopy in solution. A cis-vinylogous residue promotes an NH to CO intramolecular H-bond, closing a nine-membered pseudocycle that stabilizes a folded moiety that we proposed to name the cis-vinylogous turn. A trans-vinylogous residue involves an extended conformation. Two consecutive vinylogous residues retain their own structural propensity: "Xaa(tr)"-"Xaa(cis)" or "Xaa(cis)"-"Xaa(tr)" sequence is singly folded, whereas "Xaa(cis)"-"Xaa(cis)" sequence is doubly folded. Oligo vinylogs with all-trans or all-cis or alternating cis-trans motifs could constitute new classes of foldamers.

Crystallography, X-Ray↗
PubMed2005

Stereoselective synthesis and glycosidase inhibitory activity of 3,4-dihydroxy-pyrrolidin-2-one, 3,4-dihydroxy-piperidin-2-one and 1,2-dihydroxy-pyrrolizidin-3-one.

3,4-Dihydroxy-pyrrolidin-2-one, 3,4-dihydroxy-piperidin-2-one and 1,2-dihydroxy-pyrrolizidin-3-one have been synthesized, using a simple strategy based on the asymmetric dihydroxylation of vinylogous aminoesters and subsequent mild intramolecular cyclization. All these compounds show a partial inhibition of alpha-glucosidase, but were inactive towards other glycosidases.

Crystallography, X-Ray↗
PubMed2004

Synthesis and structure of symmetrical bicyclic hexapeptides bridged by metathesis reaction.

[structure: see text] Bicyclic hexapeptides 1a-c were synthesized via an intramolecular ring-closing metathesis reaction on solid phase followed by an N- to C-terminal cyclization in solution. Structural elucidation showed that these compounds assumed a C2-symmetrical structure with two beta-turns. The trans-ethylene plane was found to occupy two positions in rapid interconversion. One of the bicyclic hexapeptides crystallized with five water molecules, which made an arch above the ethylene group.

Cyclization↗
PubMed2004

Expression, purification, crystallization and preliminary X-ray diffraction data of methylmalonate-semialdehyde dehydrogenase from Bacillus subtilis.

Methylmalonate-semialdehyde dehydrogenase from Bacillus subtilis was cloned and overexpressed in Escherichia coli. Suitable crystals for X-ray diffraction experiments were obtained by the hanging-drop vapour-diffusion method using ammonium sulfate as precipitant. The crystals belong to space group P2(1)2(1)2(1), with unit-cell parameters a = 195.2, b = 192.5, c = 83.5 A, and contain one tetramer per asymmetric unit. X-ray diffraction data were collected to 2.5 A resolution using a synchrotron-radiation source. The crystal structure was solved by the molecular-replacement method.

Aldehyde Oxidoreductases↗
PubMed2004

tert-Butyl (6S)-4-hydroxy-6-isobutyl-2-oxo-1,2,5,6-tetrahydropyridine-1-carboxylate and tert-butyl (4R,6S)-4-hydroxy-6-isobutyl-2-oxopiperidine-1-carboxylate.

X-ray studies reveal that tert-butyl (6S)-6-isobutyl-2,4-dioxopiperidine-1-carboxylate occurs in the 4-enol form, viz. tert-butyl (6S)-4-hydroxy-6-isobutyl-2-oxo-1,2,5,6-tetrahydropyridine-1-carboxylate, C14H23NO4, when crystals are grown from a mixture of dichloromethane and pentane, and has an axial orientation of the isobutyl side chain at the 6-position of the piperidine ring. Reduction of the keto functionality leads predominantly to the corresponding beta-hydroxylated delta-lactam, tert-butyl (4R,6S)-4-hydroxy-6-isobutyl-2-oxopiperidine-1-carboxylate, C14H25NO4, with a cis configuration of the 4-hydroxy and 6-isobutyl groups. The two compounds show similar molecular packing driven by strong O-H...O=C hydrogen bonds, leading to infinite chains in the crystal structure.

Journal Article↗
PubMed2004

(6S)-6-Isobutylpiperidine-2,4-dione and (4R,6S)/(4S,6S)-4-hydroxy-6-isobutylpiperidin-2-one.

The crystal structure of (6S)-6-isobutylpiperidine-2,4-dione, C9H15NO2, shows that the keto tautomer is favoured in the solid state. The reduction of the keto functionality leads to the corresponding 4-hydroxy-6-isobutylpiperidin-2-one, C9H17NO2, with an 84:16 cis/trans ratio, containing the 4R,6S and 4S,6S isomers; the ratio of the two isomers was determined by NMR analysis of the reaction mixture. Crystals obtained from the mixture of both isomers have been studied and shown to contain the isomers in a 86:14 ratio. Hence, both X-ray and NMR analyses show that crystallization does not select the major diastereomer formed by the reduction. In both crystal structures, the two independent molecules dimerize through an R2(2)(8) hydrogen-bond motif between adjacent amide groups.

Journal Article↗
PubMed2003

Crystal structure of two ternary complexes of phosphorylating glyceraldehyde-3-phosphate dehydrogenase from Bacillus stearothermophilus with NAD and D-glyceraldehyde 3-phosphate.

The crystal structure of the phosphorylating glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from Bacillus stearothermophilus was solved in complex with its cofactor, NAD, and its physiological substrate, D-glyceraldehyde 3-phosphate (D-G3P). To isolate a stable ternary complex, the nucleophilic residue of the active site, Cys(149), was substituted with alanine or serine. The C149A and C149S GAPDH ternary complexes were obtained by soaking the crystals of the corresponding binary complexes (enzyme.NAD) in a solution containing G3P. The structures of the two binary and the two ternary complexes are presented. The D-G3P adopts the same conformation in the two ternary complexes. It is bound in a non-covalent way, in the free aldehyde form, its C-3 phosphate group being positioned in the P(s) site and not in the P(i) site. Its C-1 carbonyl oxygen points toward the essential His(176), which supports the role proposed for this residue along the two steps of the catalytic pathway. Arguments are provided that the structures reported here are representative of a productive enzyme.NAD.D-G3P complex in the ground state (Michaelis complex).

Amino Acid Substitution↗
PubMed2002

A pipecolic acid (Pip)-containing dipeptide, Boc-D-Ala-L-Pip-NH(i)Pr.

The title dipeptide, 1-(tert-butoxycarbonyl-D-alanyl)-N-isopropyl-L-pipecolamide or Boc-D-Ala-L-Pip-NH(i)Pr (H-Pip-OH is pipecolic acid or piperidine-2-carboxylic acid), C(17)H(31)N(3)O(4), with a D-L heterochiral sequence, adopts a type II' beta-turn conformation, with all-trans amide functions, where the C-terminal amide NH group interacts with the Boc carbonyl O atom to form a classical i+3 --> i intramolecular hydrogen bond. The C(alpha) substituent takes an axial position [H(alpha) (Pip) equatorial] and the trans pipecolamide function is nearly planar.

Journal Article↗
PubMed2002

Influence of silaproline on peptide conformation and bioactivity.

The analogue gamma-(dimethylsila)-proline, denoted silaproline (Sip), was synthesized in both enantiomerically pure forms by diastereoselective alkylation of a chiral glycine equivalent with use of Schöllkopf's bis-lactim ether method. The effect of replacing a proline residue in model peptides by this new proline surrogate has been examined in the crystal state by X-ray diffraction and in solution by IR absorption and NMR techniques. Silaproline and proline-containing sequences exhibit very similar conformational properties. Silaproline was also substituted for proline in a neurotensin (8-13) analogue that retained biological activity and exhibited enhanced resistance to biodegradation.

Animals↗
PubMed2002

Thioredoxins and related proteins in photosynthetic organisms: molecular basis for thiol dependent regulation.

Thioredoxins are small molecular weight disulfide oxidoreductases specialized in the reduction of disulfide bonds on other proteins. Generally, the enzymes which are selectively and reversibly reduced by these proteins oscillate between an oxidized and inactive conformation and a reduced and active conformation. Thioredoxin constitutes the archetype of a family of protein disulfide oxidoreductases which comprises glutaredoxin and protein disulfide isomerase. Thioredoxin and glutaredoxin serve many roles in the cell, including the redox regulation of target enzymes and transcription factors. They can also serve as hydrogen donors to peroxiredoxins, recently discovered heme free peroxidases, the function of which is to get rid of hydroperoxides in the cell. This review describes the molecular basis for the functioning and interaction between these enzymes in photosynthetic organisms.

Animals↗