Glycan foldamers: designing oligosaccharides to build three-dimensional architectures

Project Information

GLYCOFOLD

Grant agreement ID: 101075357

DOI

10.3030/101075357

EC signature date 21 November 2022

Start date 1 January 2023

End date 31 December 2027

Funded under

• European Research Council (ERC)

Total cost

€ 1 499 956,25

EU contribution

€ 1 499 956,00

Coordinated by

MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Germany

Periodic Reporting for period 1 - GLYCOFOLD (Glycan foldamers: designing oligosaccharides to build three-dimensional architectures)

Reporting period: 2023-01-01 to 2025-06-30

Summary of the context and overall objectives of the project

Natural biopolymers have inspired the development of synthetic analogues – i.e. foldamers – capable of adopting defined conformations and forming programmable three-dimensional architectures. These compounds are mainly based on peptides and nucleic acids, that are well understood at the molecular level. The diversity, intrinsic chirality, and ability to generate hierarchical assemblies suggest that carbohydrates hold an even larger potential for the generation of three-dimensional structures. However, the complexity of carbohydrate synthesis and structural analysis have prevented access to synthetic carbohydrates capable of adopting defined geometries.
Within GLYGOFOLD we develop carbohydrate foldamers capable of 1) adopting rigid secondary structures and 2) assembling into supramolecular architectures. To achieve these goals, we address fundamental questions related to carbohydrate structure, design new methods to stabilize particular conformations, and we implement protocols for systematic structural analysis. To complete this ambitious project, we combine automated synthetic platforms and analytical techniques (i.e. NMR spectroscopy, electron microscopy, and single molecule imaging).
Our aim is to develop programmable carbohydrate architectures, which have the potential to open a new field of carbohydrate and supramolecular chemistry. Analogous to the birth of a new field after the discovery of peptide-based foldamers, carbohydrate foldamers could find applications in several areas, including material science, biology, and catalysis. Moreover, carbohydrate foldamers will expand our understanding of carbohydrate structures and interactions, and new analytical protocols will standardize the characterization of carbohydrate materials.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

With the first period of GLYCOFOLD, we successfully designed a glycan that can fold into a stable secondary structure, challenging the traditional belief that glycans are too flexible to fold. By utilizing natural glycan motifs and stabilizing them with hydrogen bonds and hydrophobic interactions, we created a glycan hairpin, a structure never observed in nature. Our study revealed that specific chemical modifications and interactions between glycans are crucial for maintaining this folded structure. Building on this, we explored the dynamic potential of glycan hairpins by incorporating ionic groups, enabling the structures to open and close in response to environmental changes like pH or enzymes. This adaptability was confirmed through advanced imaging techniques, marking a significant step in developing responsive glycan-based materials. Additionally, we developed glycan foldamers that mimic natural catalysts, demonstrating that glycans can accelerate chemical reactions, similar to proteins, by leveraging their structural rigidity and ability to interact with other molecules. Finally, we explored the self-assembly of synthetic oligosaccharides into complex nanostructures, showing that precise control over their sequence can lead to programmable materials.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

We developed a novel synthetic approach, enzyme-triggered assembly (ETA), which allowed for the creation of long oligosaccharides previously inaccessible due to solubility and aggregation issues. This breakthrough enabled the synthesis of complex glycan structures and opens new possibilities for creating programmable glycomaterials. Our work also introduced advanced analytical protocols to accurately determine the three-dimensional structures of glycans. Additionally, we have pioneered computational tools that utilize molecular dynamics simulations to explore vast glycan chemical spaces, identifying sequences capable of folding into novel secondary structures. These innovations not only challenge the traditional view of glycans as flexible molecules but also demonstrate their potential as functional catalysts, akin to proteins. To ensure further uptake and success, key needs include continued research to refine synthetic and analytical methods. These improvements will open new avenues for the exploitation of glycans in material science and catalysis, highlighting their potential beyond traditional biological roles.