Multivalent Elastin-Like Glycopolypeptides: Subtle Chemical Structure Modifications with High Impact on Lectin Binding Affinity

Abstract

A library of synthetic elastin-like glycopolypeptides was synthesized and screened by microscale thermophoresis to identify key structural parameters affecting lectin binding efficacy. While polypeptide backbone' size and glycovalency were found to have little influence, the presence of a linker at the anomeric position of galactose and absence of positive charge on the polypeptide residue holding the sugar unit were found critical for the binding to RCA120. MAIN TEXT:Found in most organisms and involved in many different cellular processes, glycoproteins constitute a wide family of natural biomacromolecules composed of glycans covalently attached to proteins. Glycoproteins play crucial roles in major biological phenomena such as infection, cellular recognition and signal transduction. 1, 2 Carbohydrates in glycoproteins interact with a specific class of proteins, termed lectins, through weak monomeric interactions, the high binding affinity between a specific glycoprotein and a lectin being insured by the architecture of the protein and by the presentation of the carbohydrate ligands in a multivalent manner, a phenomenon termed as the "glycoside cluster effect". 3,4 Considerable efforts have been made to synthesize glycoprotein mimics as powerful tools for glycobiology or as lead compounds for therapeutic applications. A wide variety of scaffolds have been explored to access multivalent glycoarchitectures, 5 dendrimers and polymers being the widest families of synthetic compounds explored so far. Polymer chemistry affords myriads of possibilities in terms of glycopolymer design: different architectures can be engineered, chain lengths, sugar numbers and sugar density can also be tuned to increase the potency of glycopolymers towards specific lectins. 6 Because any polymer backbone may not closely mimic the chemical structure of glycoproteins, particular attention was paid to glycopolymers composed of polypeptide backbones decorated with pendant carbohydrates, so designated as glycopolypeptides, as simplified analogues of glycoproteins. [7][8][9][10] Glycopolypeptides obtained by polymerization techniques are accessible at large scales 7,11,12 and impressive advances have been made towards well-defined glycopolypeptides. Inherent macromolecular dispersity arising from polymerization techniques has also encouraged the development of unimolecular multivalent glycoconjugates. To access multivalent glycopeptides with precise compositions, scientists have explored a wide range of chemical strategies ranging from solid-phase synthesis of glycopeptides, 13, 14 ligation techniques 15, 16 or enzymatic syntheses. 5,17 Despite significant progresses, limitations still remain regarding the high complexity of these macromolecular structures and low amount of materials accessible. We believe recombinant DNA and genetic engineering are unique opportunities to access high precision polypeptides with an exact control over monomer sequence and chain length at reasonable scales, while chemoselective modification reactions can be ...

A general strategy to the intracellular sensing of glycosidases using AIE-based glycoclusters

“…Addition of Bu 4 NI and 18-crown-6 enhanced the reactivity of phenolates for a proper etherification in 92% yield to obtain the bispropargyl compound 10 (Scheme 1). Galactosides with a 3azidopropyl 44 (short-arm) or azido-triethyleneglycol 45 (longarm) aglycon were then conjugated to compound 10 in the presence of CuSO 4 /sodium ascorbate (VcNa) as catalyst. 33,46 Solvolysis of the ester protecting groups afforded the TD-CGal 2 and TD-EGGal 2 probes from compound 11 and 12, respectively (Scheme 1).…”

Refining the Design of Diblock Elastin-Like Polypeptides for Self-Assembly into Nanoparticles

“…The presence of methionine residues however allowed us to easily access and study a second family of ELPs without the design of a new ELP sequence requiring the construction of a new encoding gene and multiple molecular cloning steps. Indeed, our group has developed and applied over the past years a set of chemoselective reactions at the methionine side chain as a mean to easily tune physico-chemical properties of methionine-containing ELPs or to introduce specific pendant groups or moieties [ 41 , 42 , 47 , 48 ]. In particular, chemical oxidation of the thioether side chain into sulfoxide was found to have a major impact on the cloud point due to a drastic increase in hydrophilicity [ 49 ].…”

A General Strategy to the Intracellular Sensing of Glycosidases using AIE-Based Glycoclusters

“…Addition of Bu4NI and 18-crown-6 enhanced the reactivity of phenolates for a proper etherification in 92% yield to obtain the bis-propargyl compound 10 (Scheme 1). Galactosides with a 3-azidopropyl 57 (short-arm) or azido-triethyleneglycol 58 (long-arm) aglycon were then conjugated to compound 10 in the presence of CuSO4/sodium ascorbate (VcNa) as catalyst. 46,59 Solvolysis of the ester protecting groups afforded the TD-CGal2 and TD-EGGal2 probes from compound 11 and 12, respectively.…”