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Affinity enhancement by dendritic side chains in synthetic carbohydrate receptors.

ABSTRACT: Dendritic side chains have been used to modify the binding environment in anthracene-based synthetic carbohydrate receptors. Control of length, charge, and branching enabled the positioning of side-chain carboxylate groups in such a way that they assisted in binding substrates rather than blocking the cavity. Conformational degeneracy in the dendrimers resulted in effective preorganization despite the flexibility of the system. Strong binding was observed to glucosammonium ions in water, with Ka values up to 7000 M(-1) . Affinities for uncharged substrates (glucose and N-acetylglucosamine) were also enhanced, despite competition from solvent and the absence of electrostatic interactions.

SUBMITTER: Destecroix H

PROVIDER: S-EPMC4506558 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Affinity enhancement by dendritic side chains in synthetic carbohydrate receptors.

Destecroix Harry H Renney Charles M CM Mooibroek Tiddo J TJ Carter Tom S TS Stewart Patrick F N PF Crump Matthew P MP Davis Anthony P AP

Angewandte Chemie (International ed. in English) 20150121 7

Dendritic side chains have been used to modify the binding environment in anthracene-based synthetic carbohydrate receptors. Control of length, charge, and branching enabled the positioning of side-chain carboxylate groups in such a way that they assisted in binding substrates rather than blocking the cavity. Conformational degeneracy in the dendrimers resulted in effective preorganization despite the flexibility of the system. Strong binding was observed to glucosammonium ions in water, with Ka ...[more]

PMID: 25645064

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Project description:SYNTHETIC CANCER VACCINES: A number of fully synthetic vaccine candidates have been designed, chemically synthesized, and immunologically evaluated to establish a strategy to overcome the poor immunogenicity of tumor-associated carbohydrates and glycopeptides and to determine the importance of Toll-like receptor (TLR) engagement for antigenic responses against these compounds.Epithelial cancer cells often overexpress mucins that are aberrantly glycosylated. Although it has been realized that these compounds offer exciting opportunities for the development of immunotherapy for cancer, their use is hampered by the low antigenicity of classical immunogens composed of a glycopeptide derived from a mucin conjugated to a foreign carrier protein. We have designed, chemically synthesized, and immunologically evaluated a number of fully synthetic vaccine candidates to establish a strategy to overcome the poor immunogenicity of tumor-associated carbohydrates and glycopeptides. The compounds were also designed to allow study of the importance of Toll-like receptor (TLR) engagement for these antigenic responses in detail. We have found that covalent attachment of a TLR2 agonist, a promiscuous peptide T-helper epitope, and a tumor-associated glycopeptide gives a compound (1) that elicits in mice exceptionally high titers of IgG antibodies that recognize MCF7 cancer cells expressing the tumor-associated carbohydrate. Immunizations with glycolipopeptide 2, which contains lipidated amino acids instead of a TLR2 ligand, gave significantly lower titers of IgG antibodies; this demonstrates that TLR engagement is critical for optimum antigenic responses. Although mixtures of compound 2 with Pam(3)CysSK(4) (3) or monophosphoryl lipid A (4) elicited titers of IgG antibodies similar to those seen with 1, the resulting antisera had impaired ability to recognize cancer cells. It was also found that covalent linkage of the helper T-epitope to the B-epitope is essential, probably because internalization of the helper T-epitope by B-cells requires assistance of the B-epitope. The results presented here show that synthetic vaccine development is amenable to structure-activity relationship studies for successful optimization of carbohydrate-based cancer vaccines.

Project description:Amino acid side-chain conformational properties influence the overall structural and dynamic properties of proteins and, therefore, their biological functions. In this study, quantum mechanical (QM) potential energy surfaces for the rotation of side-chain χ(1) and χ(2) torsions in dipeptides in the alphaR, beta, and alphaL backbone conformations were calculated. The QM energy surfaces provide a broad view of the intrinsic conformational properties of each amino acid side-chain. The extent to which intrinsic energetics dictates side-chain orientation was studied through comparisons of the QM energy surfaces with χ(1) and χ(2) free energy surfaces from probability distributions obtained from a survey of high resolution crystal structures. In general, the survey probability maxima are centered in minima of the QM surfaces as expected for sp(3) (or sp(2) for χ(2) of Asn, Phe, Trp, and Tyr) atom centers with strong variations between amino acids occurring in the energies of the minima indicating intrinsic differences in rotamer preferences. High correlations between the QM and survey data were found for hydrophobic side-chains except Met, suggesting minimal influence of the protein and solution environments on their conformational distributions. Conversely, low correlations for polar or charged side-chains indicate a dominant role of the environment in stabilizing conformations that are not intrinsically favored. Data also link the presence of off-rotamers in His and Trp to favorable interactions with the backbone. Results also suggest that the intrinsic energetics of the side-chains of Phe and Tyr may play important roles in protein folding and stability. Analyses on whether intrinsic side-chain energetics can influence backbone preference identified a strong correlation for residues in the alphaL backbone conformation. It is suggested that this correlation reflects the intrinsic instability of the alphaL backbone such that assumption of this backbone conformation is facilitated by intrinsically favorable side-chain conformations. Together our results offer a broad overview of the conformational properties of amino acid side-chains and the QM data may be used as target data for force field optimization.

Dataset Information

Affinity enhancement by dendritic side chains in synthetic carbohydrate receptors.

Publications

Affinity enhancement by dendritic side chains in synthetic carbohydrate receptors.

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