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Developing arylamide foldamers as new platforms for glycan microarray technology
Publication . Pinheiro, Gonçalo Manuel Silva de Almeida; Mateus, Pedro; Palma, Angelina
Glycan microarrays are powerful tools for investigating the carbohydrate-binding specificity of proteins and antibodies, identifying potential drug targets, and detecting biomarkers that may indicate disease states. These arrays typically feature glycan sequences attached to a surface using a linker at the glycan’s reducing end. However, the spatial arrangement of glycans on a cell surface differs significantly from that on a synthetic glycoarray. Glycoconjugate mimetics, which position glycans similarly to natural glycoproteins, can be integrated into arrays to create a more physiologically relevant platform for probing glycan-binding proteins. However, few allow precise control over the number, orientation, and distance between glycans.
This project aimed to design and synthesized arylamide foldamers—oligomers containing aromatic amide segments—as a new platform for the multivalent display of carbohydrates, suitable for integration with current microarray technology platforms. The key features of arylamide foldamers are expected to offer distinct advantages, as the densities and orientations of glycan ligands are dictated by their structure rather than the unclear characteristics of conventional glycan arrays.
To provide proof-of-principle, a sequence of five monomers was designed to form a single-strand helix spanning two turns, featuring an alkyne side chain to enable the conjugation of an α-mannose ligand or a fluorophore via copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC), along with a free amine group to allow covalent immobilization onto NHS-activated glass slides.
To prepare the envisioned compounds, it was first necessary to synthesize the respective monomer units—two based on published methods and three of new design—as well as rhodamine B and α-mannose featuring azide-terminated linkers. The foldamer conjugates were then assembled through solid-phase synthesis, followed by CuAAC click chemistry.
The work described in this dissertation represents the initial steps toward the integration of glycofoldamers into microarray technology and will serve as a foundation for future advancements.
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Fundação para a Ciência e a Tecnologia
Programa de financiamento
3599-PPCDT
Número da atribuição
2022.03561.PTDC