Molecular Modeling Studies of Peptide Based Lectinomimics

摘要

Carbohydrates mediate numerous biological processes involving cell-cell recognition. Concurrently, establishing connections between glycan structures and their functions has fuelled strong interest in mimicking the action of lectins, carbohydrate binding proteins, for potential bioanalytical and/or biomedical applications. Cyclic peptides represent a particularly attractive approach for the design and preparation of artificial carbohydrate receptors [1]. Peptide cyclization lowers the conformational flexibility that might lead to the formation of less entropically unfavorable conformations in order to adopt the optimal complex geometry. It has been reported recently that small cyclic peptides possessing a β-turn/β-sheet conformation display lectin-like properties. The simplest of these is odorranalectin, a 17-mer cyclic peptide containing one disulfide bond isolated from skin secretions of the frog Odorrana grahami (Figure 1) [2]. Odorranalectin natural product was found to selectively bind to L-fucose with a binding affinity (K_d) of 55 uM [2]. Selectivity and affinity of peptide based lectinomimic can be tuned by the sequence modification. In particular, modification using a combinatorial chemistry approach offers enormous potential for synthesis of new and more selective peptide based lectinomimics. In the case of odorranalectin combinatorial library, Cys residues have to be omitted from the sequence in order to avoid potential problems with the thiol group oxidation during the library synthesis. However, substitution of disulphide bond in odorranalectin with other linkers may affect its conformation and thus its ability to form a hydrophobic pocket required for binding of carbohydrate ligands. To assess the effect of the disulphide bond substitution with different linkers on odorranalectin's conformation, we performed a conformational analysis of the natural product as well as a series of analogs with amide, diazine, diselenium, ethyne, ethane and thioether linkers (Figure 2a).