C-Glycosyl α-Amino Acids as Structural Encoders of Peptide Conformation

Bogović, Barbara; Colić, Ivana; Nikšić-Franjić, Ivana; Smrečki, Vilko; Jerić, Ivanka (2025) C-Glycosyl α-Amino Acids as Structural Encoders of Peptide Conformation. Angewandte Chemie International Edition . ISSN 1433-7851 (In Press)

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Official URL: https://onlinelibrary.wiley.com/doi/10.1002/anie.2...

Abstract

C-glycosylation is a well-established strategy for improving the pharmacokinetic properties of peptides; however, the influence of chiral C-glycosyl amino acid incorporation on peptide conformation remains insufficiently explored. Most existing synthetic approaches restrict C-glycosyl amino acid placement to the N-terminus, C-terminus, or specific residues containing pre-installed reactive groups. Here, we present a more versatile strategy based on the design and synthesis of customized C-glycosyl amino acids. Four variants bearing protected galactopyranose, ribofuranose, sorbofuranose, or allofuranose side chains were synthesized and incorporated into peptides using a solid-phase methodology, enabling substitution at diverse sequence positions. Detailed NMR analyses revealed that each C-glycosyl -amino acid promotes distinct conformational preferences, primarily stabilized by hydrogen-bonding networks between backbone amides and carbohydrate side chains. These findings uncover conformational information encoded within four non-canonical C-glycosyl -amino acids, offering new molecular tools for catalysis, materials development and drug discovery.

Item Type:

Article

Uncontrolled Keywords:

C-glycosyl amino acids; C-glycopeptides; conformational analysis; NMR spectroscopy

Subjects:

NATURAL SCIENCES > Chemistry > Organic Chemistry

Divisions:

Division of Organic Chemistry and Biochemistry
NMR Center

Projects: