Foldamers in Medicinal Chemistry

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A post-elongation strategy for the introduction of guanidinium units in the main chain of helical oligourea foldamers

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Luc Courchesne : observateur du monde

Catalogue préparé sous la direction de Christine Bernier.Catalogue de l’exposition tenue au Carrefour des arts et des sciences, Université de Montréal, du 13 avril au 19 juin 2022

Methods Enzymol

N,N'-linked oligoureas are a class of enantiopure, sequence-defined peptidomimetic oligomers without amino acids that form well-defined and predictable helical structures akin to the peptide α-helix. Oligourea-based foldamers combine a number of features-such as synthetic accessibility, sequence modularity, and folding fidelity-that bode well for their use in a range of applications from medicinal chemistry to catalysis. Moreover, it was recently recognized that this synthetic helical backbone can be combined with regular peptides to generate helically folded peptide-oligourea hybrids that display additional features in terms of helix mimicry and protein-surface recognition properties. Here we provide detailed protocols for the preparation of requested monomers and for the synthesis and purification of homo-oligoureas and peptide-oligourea hybrids.Hélices chimériques aux propriétés innovantes pour l'inhibition des interactions protéine-protéineMimétisme et ingénierie d'enzymes artificielles à l'aide de foldamère

Postelongation Strategy for the Introduction of Guanidinium Units in the Main Chain of Helical Oligourea Foldamers

The synthesis of hybrid urea-based foldamers containing isosteric guanidinium linkages at selected positions in the sequence is described. We used a postelongation approach whereby the guanidinium moiety is introduced by direct transformation of a parent oligo­(urea/thiourea) foldamer precursor. The method involves activation of the thiourea by treatment with methyl iodide and subsequent reaction with amines. To avoid undesired cyclization with the preceding urea moiety, resulting in heterocyclic guanidinium formation in the main chain, the urea unit preceding the thiourea unit in the sequence was replaced by an isoatomic and isostructural γ-amino acid. The approach was extended to solid-phase techniques to accelerate the synthesis of longer and more functionalized sequences. Under optimized conditions, an octamer hybrid oligomer incorporating a central guanidinium linkage was obtained in good overall yield and purity. This work also reports data related to the structural consequences of urea by guanidinium replacements in solution and reveals that helical folding is substantially reduced in oligomers containing a guanidinium group

Postelongation Strategy for the Introduction of Guanidinium Units in the Main Chain of Helical Oligourea Foldamers

The synthesis of hybrid urea-based foldamers containing isosteric guanidinium linkages at selected positions in the sequence is described. We used a postelongation approach whereby the guanidinium moiety is introduced by direct transformation of a parent oligo­(urea/thiourea) foldamer precursor. The method involves activation of the thiourea by treatment with methyl iodide and subsequent reaction with amines. To avoid undesired cyclization with the preceding urea moiety, resulting in heterocyclic guanidinium formation in the main chain, the urea unit preceding the thiourea unit in the sequence was replaced by an isoatomic and isostructural γ-amino acid. The approach was extended to solid-phase techniques to accelerate the synthesis of longer and more functionalized sequences. Under optimized conditions, an octamer hybrid oligomer incorporating a central guanidinium linkage was obtained in good overall yield and purity. This work also reports data related to the structural consequences of urea by guanidinium replacements in solution and reveals that helical folding is substantially reduced in oligomers containing a guanidinium group

Postelongation Strategy for the Introduction of Guanidinium Units in the Main Chain of Helical Oligourea Foldamers

The synthesis of hybrid urea-based foldamers containing isosteric guanidinium linkages at selected positions in the sequence is described. We used a postelongation approach whereby the guanidinium moiety is introduced by direct transformation of a parent oligo­(urea/thiourea) foldamer precursor. The method involves activation of the thiourea by treatment with methyl iodide and subsequent reaction with amines. To avoid undesired cyclization with the preceding urea moiety, resulting in heterocyclic guanidinium formation in the main chain, the urea unit preceding the thiourea unit in the sequence was replaced by an isoatomic and isostructural γ-amino acid. The approach was extended to solid-phase techniques to accelerate the synthesis of longer and more functionalized sequences. Under optimized conditions, an octamer hybrid oligomer incorporating a central guanidinium linkage was obtained in good overall yield and purity. This work also reports data related to the structural consequences of urea by guanidinium replacements in solution and reveals that helical folding is substantially reduced in oligomers containing a guanidinium group

β-Carotene bioavailability and conversion efficiency are significantly affected by sex in rats. First observation suggesting a possible hormetic regulation of vitamin A metabolism in female rats

International audienceScope: To study the effect of variation in dietary vitamin A (VA) content on its hepatic and intestinal metabolism. Methods and results: Adult female and male rats were fed with diets containing 400, 2300, or 9858 IU/kg VA for 31-33 weeks. VA concentrations were measured in plasma and liver. Bioavailability and intestinal conversion efficiency of β-carotene to VA were assessed by measuring postprandial plasma β-carotene and retinyl palmitate concentrations after force-feeding rats with β-carotene. Expression of genes involved in VA metabolism, together with concentrations of RBP4, BCO1 and SR-BI proteins, were measured in the intestine and liver of female rats. Plasma retinol concentrations were lower and hepatic free retinol concentrations were higher in females than in males. There was no effect of dietary VA content on β-carotene bioavailability and its conversion efficiency, but bioavailability was higher and conversion efficiency was lower in females than in males. The expression of most genes exhibited a U-shaped dose response curve depending on VA intake. Main conclusions: β-Carotene bioavailability and conversion efficiency to VA are affected by the sex of rats. Results of gene expression suggest a hormetic regulation of VA metabolism in female rats

Adaptive Binding of Alkyl Glycosides by Nonpeptidic Helix Bundles in Water: Toward Artificial Glycolipid Binding Proteins

International audienceAmphipathic water-soluble helices formed from synthetic peptides or foldamers are promising building blocks for the creation of self-assembled architectures with non-natural shapes and functions. While rationally designed artificial quaternary structures such as helix bundles have been shown to contain preformed cavities suitable for guest binding, there are no examples of adaptive binding of guest molecules by such assemblies in aqueous conditions. We have previously reported a foldamer 6-helix bundle that contains an internal nonpolar cavity able to bind primary alcohols as guest molecules. Here, we show that this 6-helix bundle can also interact with larger, more complex guests such as n-alkyl glycosides. X-ray diffraction analysis of co-crystals using a diverse set of guests together with solution and gas-phase studies reveals an adaptive binding mode whereby the apo form of the 6-helix bundle undergoes substantial conformational change to accommodate the hydrocarbon chain in a manner reminiscent of glycolipid transfer proteins in which the cavity forms upon lipid uptake. The dynamic nature of the self-assembling and molecular recognition processes reported here marks a step forward in the design of functional proteomimetic molecular assemblies

Vitamin A deficiency during the perinatal period induces changes in vitamin A metabolism in the offspring. The regulation of intestinal vitamin A metabolism via ISX occurs only in male rats severely vitamin A-deficient

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