Why Structurally Different Cyclic Peptides Can Be Glycomimetics of the HNK-1 Carbohydrate Antigen

Abstract

The cyclic peptides c-(LSETTl) 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-(LSETTl) 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-(LSETTl), and c-(RTLPFS) with a laminin fragment involved in HNK-1 carbohydrate binding (i.e., the 21mer 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 HNK-1-binding 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 cyclopeptides c-(LSETTl) and c-(RTLPFS) with a reliable receptor structure in considerable detail.

Computational Screening of the Human TF-Glycome Provides a Structural Definition for the Specificity of Anti-Tumor Antibody JAA-F11

“…In the case of JAA-F11, the 3D model can be further employed to guide the rational design of peptide mimotopes of the carbohydrate, for use as immunogens[30], [31], [32], [33], as well as to guide the selection of key residues to be included during antibody humanization. Humanization of a mouse mAb by insertion of the CDRs into a human antibody scaffold, can lead to changes in the 3D conformation, particularly in the interface between the variable light and heavy chains[34], with a corresponding loss of affinity or specificity.…”

Structure–Activity Relationship Studies, SPR Affinity Characterization, and Conformational Analysis of Peptides That Mimic the HNK‐1 Carbohydrate Epitope

“…Coming back to our design strategy, we hypothesized that the carboxylic functions of the two Glu residues of our peptide might mimic the negatively charged functional groups of the HNK‐1 trisaccharide. However, previously published molecular dynamics (MD) simulations revealed that the distance between the negative groups of HNK‐1 is rather stable, at ∼6 Å . In contrast, distance between the carboxylates of peptide 5 varies between 9.0 and 12.0 Å in our calculated ensemble.…”

Identification of Peptide Mimics of a Glycan Epitope on the Surface of Parasitic Nematode Larvae

“…We found that most peptides were recognised by antibodies in saliva to some degree, which provided additional evidence for the selection of biologically-relevant mimotopes, although their amino acid sequences differed. This is not too surprising as several glycomimetic cyclic peptides can exhibit similar physico-chemical properties to their surrogate carbohydrate molecule [14]. …”