Pascal Dumy

Chemo- and stereoselective glycosylation of hydroxylamino derivatives: A versatile approach to glycoconjugates

A general method for the stereoselective coupling of unprotected oligosaccharides with any substrate containing a N,O-disubstituted hydroxylamine group is described. The cyclic nature of the oligosaccharide reducing unit is preserved and the substrate glycosylated with high diastereoselectivity to sugar through an amino (N[OR2]-) or an aminoxy (N[R-1]-O-) linkage. Due to the uniquely high chemical reactivity and specificity of disubstituted hydroxylamine toward the sugar reducing end, neither protecting groups nor activation methods are required to perform the reaction in aqueous solution. The characteristic features and the scope of this new type of glycosylation reaction are exemplified for the chemoselective synthesis of model glycopeptides

A CONVENIENT SYNTHESIS OF CYCLIC-PEPTIDES AS REGIOSELECTIVELY ADDRESSABLE FUNCTIONALIZED TEMPLATES (RAFT)

Cyclic decapeptides containing up to four orthogonally protected lysine residues have been efficiently prepared by a combined solid phase and solution strategy. These cyclic peptides represent new Regioselectively Addressable Functionalized Templates (RAFT), which are suitable for use in protein de novo design according to the TASP concept.

Solution structure of regioselectively addressable functionalized templates: an NMR and restrained molecular dynamics investigation.

Three cyclic peptides that are Regioselectively Addressable Functionalized Templates (RAFT) for use in protein de novo design have been investigated using a combination of nmr, restrained molecular dynamics, and CD spectroscopy. These peptides contain up to four selectively addressable sites (orthogonally protected lysine side chains) or have selectively addressable faces. The results show a common stable conformation for templates of this kind based on two type II beta-turns and an associated beta-sheet structure. A preferential orientation for the side chains is also demonstrated. The significance of these findings is discussed in the context of applications of RAFT that rely on their conformational rigidity and ability to present functionalities in a defined spatial arrangement.

Reversible oriented immobilization of histidine-tagged proteins on gold surfaces using a chelator thioalkane

The authors present the results on specific and non-specific protein binding to the self-assembled chelator thioalkane layer and its dependence on the transition metal ion used. [on SciFinder (R)]

Functional molecular thin films: topological templates for the chemoselective ligation of antigenic peptides to self-assembled monolayers

The combination of self-assembly and regioselective surface chemistry has made it possible to immobilize peptide recognition sites 1 on a template attached to a gold surface. Each of the seven individual reaction steps, including the final functional biomolecular recognition, was controlled in situ with surface-sensitive detection techniques. The presented strategy is of general importance for the formation of complex supramolecular structures with biologically interesting functionalities at the interfaces.

Protein design: On the threshold of functional properties

The ultimate goal in protein de novo design is the creation of novel macromolecules with tailor-made receptor, sensory, and catalytic functions. Despite considerable progress in understanding basic rules of secondary structure formation and protein stability, the well-known protein folding problem is still far from being solved and, in general, only a limited number of designed proteins are folded uniquely. In this article the state-of-the-art in protein design is demonstrated on some selected examples, indicating that the construction of protein-like macromolecules mimicking some essential features of natural proteins seems to be within reach. Thus, protein design and mimicry has become an interdisciplinary challenge with most intriguing perspectives.

Pseudo-prolines in cyclic peptides: Conformational stabilisation of cyclo[Pro-Thr(ψMe,Mepro)-Pro]

Linear peptide H-Pro-Thr(Psi(Me,Me)pro)-Pro-OH containing a preformed cis-Pro-Thr(Psi(Me,Me)pro) tertiary amide bond cyclises instantaneously and free of formation of oligomeric structures to the cyclic tripeptide cyclo-[Pro-Thr(Psi(Me,Me)pro)-Pro]. Even at concentrations up to 10(-1) M peptide, no oligomeric structures are detected by mass spectroscopy and HPLC. 2D H-1 NMR studies of purified cyclotripeptide reveal the compound to exist in one single conformation with all peptide bonds in the cis conformation. These results indicate enhanced cyclisation tendencies of cis-amide bond containing peptides of short chain length

Hydrazinolysis of Dde: Complete orthogonality with aloc protecting groups

Hydrazinolysis of Dde group is troublesome in the presence of Aloc protected peptides. We elucidate that reduction of the Aloc double bond occurs both in solution and on solid support preventing the subsequent Aloc deprotection and resulting in mixtures difficult to purify. We report here that addition of allyl alcohol as scavenger circumvents this side reaction and provides a complete orthogonality between Dde and Aloc in solution and solid phase peptide synthesis

Lysine as helix C-capping residue in a synthetic peptide

The structure of the synthetic peptide CH3CO(Leu-Ser-Leu-Leu-Leu-Ser-Leu)3Lys-NH2 in trifluoroethanol/water 60/40 (volume ratio) was characterized by two-dimensional nmr spectroscopy. The peptide, closely related to the amphiphilic helix models designed by W. F. De-Grado and co-workers to mimic protein ion channels [(1988) Science, Vol. 240, p. 1177-1181], folds into a regular helix spanning residues 1-20. Evidence for a helix C-terminal capping conformation, involving the terminal lysine residue, was observed from Overhauser effects and checked for consistency by restrained molecular dynamics simulations. The side-chain amino group of Lys22 forms a hydrogen bond with the carbonyl of Leu18, and the distorted helical geometry of the terminal dipeptide allows the inclusion of a water bridge between the backbone NH of the Lys22 residue and the carbonyls of Leu19 and Ser20.

Pseudoprolines (Pro) in Drug Design: Direct Insertion of Pro Systems into Cyclosporin C

The insertion of acetals that exhibit variable structural features into complex peptides such as cyclosporin C (CsC) results in oxazolidine derivatives (pseudoprolines, Psi Pro) of tailored physico-chemical and biological properties. N,O-Acetalation of the 2-threonine hydroxyl group and the preceding amide nitrogen of CsC is achieved by treating the molecule with a number of both arylated and non-arylated dimethyl acetals. The Psi Pro-containing CsC derivatives exhibit enhanced conformational backbone rigidity, as suggested by analytical HPLC, NMR spectroscopy and by kinetic measurements on binding with their receptor protein cyclophilin A (CypA) that were not time-dependent. IC50 values for calf-thymus CypA were obtained by kinetic evaluation of its cis --> trans isomerase activity. The choice of the pam-substituted aryl dimethyl acetals allows the inhibitory properties of the corresponding derivatives to be modulated to either prodrugs or moderately strongly binding cyclosporin C derivatives.