Glycomimetics: a programmed approach toward neoglycopeptide libraries.

A programmed synthesis of neoglycopeptides has been developed in which two, similar or different, glycoside moieties could be attached either (i) at the N-terminal of short peptides or (ii) one at the N-internal and the other(s) at the N-terminal site, in a highly flexible and controlled manner. A stepwise branching of N-terminal peptides has been achieved by glycoside aldehyde reductive amination followed by the glycoside carboxylic acid coupling (model 1). In another approach, after N-alkylation with glycoside aldehyde, the N-glycosylated derivative is subjected to peptide synthesis. This is then followed by the attachment of the second glycoside moiety at the N-terminal using either glycoside aldehyde or glycoside carboxylic acid derivative (model 2). Alternatively, the attachment of second and third glycoside derivatives could be achieved simultaneously, by reductive amination/carboxylic acid couplings (model 3). The methodologies presented here are highly versatile and combine diversity in both peptides/pseudopeptides and glycoside moieties.

Alpha-galactose based neoglycopeptides. Inhibition of verotoxin binding to globotriosylceramide.

Solution and solid phase strategies for the synthesis of alpha-galactose based neoglycopeptide derivatives 2-13 were developed. Neoglycopeptides generated were tested for the inhibition of verotoxin binding to globotriosylceramide (Gb3) using ELISA. Among all of the compounds tested, only the lipid derivatives of neoglycopeptides, 11, 12 and 13 were found to be inhibitors, IC50 = 2.0 mM (11b and 12c) and 0.2 mM (11c and 13c). All of the inhibitors (11b, 11c, 12c and 13c) have a similar branching of the two alpha-galactosyl units at the N-terminal glycine residue of a short peptide and a lipid moiety attached at the C-terminal site. Both of these factors seem to be crucial for the inhibition. It is interesting to note that the inhibitors have only a portion of the natural trisaccharide ligand. The secondary groups either may contribute in sub-site oriented interactions with the protein receptors or may mimic the internal sugar units of the cell-surface ligand, Gb3.

Diversity of C-linked neoglycopeptides for the exploration of subsite-assisted carbohydrate binding interactions.

Diversity of alpha-galactose based C-linked neoglycopeptides (1b, 2b, 3c, 4d, and 5d) has been developed to explore the importance of subsite-assisted carbohydrate binding interactions. Deprotected C-linked neoglycopeptides (1b, 2b, 3c, 4d, and 5d) were synthesized and tested in competitive inhibition assays using a model enzyme-linked lectin (e.g., Maclura pomifera). Compound 2b, with two alpha-galactoside units on the side chain of the lysine residue of the dipeptide backbone, exhibited a remarkable effect with a 2.82-fold increase in its inhibitory properties (IC50 1.48 mM) in comparison to 1b (IC50 4.18 mM).