Journal of the American Chemical Society, Vol.132, No.1, 96-105, 2010
Why Structurally Different Cyclic Peptides Can Be Glycomimetics of the HNK-1 Carbohydrate Antigen
The cyclic peptides c-(LSETTI) and c-(RTLPFS) are of potential clinical interest-they stimulate neurite outgrowth in a way that is similar to the effects of the HNK-1 (human natural killer cell-1) antigenic carbohydrate chains, which are terminated by 3'-sulfated glucuronic acid attached to an N-acetyllactosamine unit. To investigate the structure-activity relationships of the ability of the cyclic peptides to mimic HNK-1 carbohydrates, conformational analysis and examination of hydrophobic and hydrophilic patterns were performed and compared with the characteristics of a synthetic HNK-1 trisaccharide derivative. Data obtained demonstrate that both the trisaccharide and the glycomimetic peptide c-(LSETTI) exhibit a similar relationship between their hydrophobic moieties and their negatively charged sites. However, the second cyclic glycomimetic peptide investigated here, c-(RTLPFS), has a positively charged group as a potential contact point due to its Arg residue. Therefore, we studied the amino acid composition of all known receptor structures in the Protein Data Bank that are in contact with uronic acid and/or sulfated glycans. Interactions of the HNK-1 trisaccharide, c-(LSETTI), and c-(RTLPFS) with a laminin fragment involved in HNK-1 carbohydrate binding (i.e., the 21 mer peptide: KGVSSRSYVGCIKNLEISRST) were also analyzed. Because the structure of the HNK-1-binding laminin domain is not available in the Protein Data Bank, we used the HNIK-1-bincling 21mer peptide fragment of laminin for the construction of a model receptor that enabled us to compare the molecular interplay of the HNK-1 trisaccharide and the two cylopeptides c-(LSETTI) and c-(RTLPFS) with a reliable receptor structure in considerable detail.