Glycomimetic cyclic peptides stimulate neurite outgrowth

Baechle D, Loers G, Guthöhrlein EW, Schachner M, Sewald N. Glycomimetic cyclic peptides stimulate neurite outgrowth. Angewandte Chemie International Edition. 2006;45(39):6582-6585

Glycomimetische Cyclopeptide stimulieren Neuritenwachstum

Bächle D, Loers G, Guthöhrlein EW, Schachner M, Sewald N. Glycomimetische Cyclopeptide stimulieren Neuritenwachstum. Angewandte Chemie. 2006;118(39):6733–6736

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

The design of molecules that mimic biologically relevant glycans is a significant goal for understanding important biological processes and may lead to new therapeutic and diagnostic agents. In this study we focused our attention on the trisaccharide human natural killer cell-1 (HNK-1), considered the antigenic determinant of myelin-associated glycoprotein and the target of clinically relevant auto-antibodies in autoimmune neurological disorders such as IgM monoclonal gammopathy and demyelinating polyneuropathy. We describe a structure-activity relationship study based on surface plasmon resonance binding affinities aimed at the optimization of a peptide that mimics the HNK-1 minimal epitope. We developed a cyclic heptapeptide that shows an affinity of 1.09×10(-7)  m for a commercial anti-HNK1 mouse monoclonal antibody. Detailed conformational analysis gave possible explanations for the good affinity displayed by this novel analogue, which was subsequently used as an immunological probe. However, preliminary screening indicates that patients' sera do not specifically recognize this peptide, showing that murine monoclonal antibodies cannot be used as a guide to select immunological probes for the detection of clinically relevant human auto-antibodies

Carbohydrate mimics promote functional recovery after peripheral nerve repair

Simova O, Irintchev A, Mehanna A, et al. Carbohydrate mimics promote functional recovery after peripheral nerve repair. ANNALS OF NEUROLOGY. 2006;60(4):430-437.Objective: The outcome of peripheral nerve repair is often unsatisfactory, and efficient therapies are not available. We tested the therapeutic potential of functional mimics of the human natural killer cell glycan (3-sulfoglucuronyl beta 1-3 galactoside) (HNK-1) epitope, a carbohydrate indicated to favor specificity of motor reinnervation in mice. Methods: We applied a linear HNK-1 mimic peptide, scrambled peptide, or vehicle substances in polyethylene cuffs used to reconstruct the severed femoral nerves of adult mice. We used video-based motion analysis and morphological and tracing techniques to monitor the outcome of nerve repair. Results: After glycomimetic application, quadriceps muscle function recovered to 93% of normal within 3 months. Restoration of function was less complete (71-76%) in control groups. Better functional recovery was associated with larger motoneuron somata, better axonal myelination in the quadriceps nerve, and enhanced precision of target reinnervation. Lesion-induced death of motoneurons was reduced by 20 to 25%. The glycomimetic enhanced survival and neurite outgrowth of both mouse and human motoneurons in vitro by 30 to 75%. Application of a novel cyclic glycomimetic also enhanced functional recovery in vivo. Interpretation: The improved outcome of nerve repair after glycomimetic application may be attributed to neurotrophic effects. Our results hold promise for therapeutic use in humans

Regulated expression and neural functions of human natural killer-1 (HNK-1) carbohydrate.

Human natural killer-1 (HNK-1) carbohydrate, comprising a unique trisaccharide HSO(3)-3GlcAβ1-3Galβ1-4GlcNAc, shows well-regulated expression and unique functions in the nervous system. Recent studies have revealed sophisticated and complicated expression mechanisms for HNK-1 glycan. Activities of biosynthetic enzymes are controlled through the formation of enzyme-complexes and regulation of subcellular localization. Functional aspects of HNK-1 carbohydrate were examined by overexpression, knockdown, and knockout studies of these enzymes. HNK-1 is involved in several neural functions such as synaptic plasticity, learning and memory, and the underlying molecular mechanisms have been illustrated upon identification of the target carrier glycoproteins of HNK-1 such as the glutamate receptor subunit GluA2 or tenascin-R. In this review, we describe recent findings about HNK-1 carbohydrate that provide further insights into the mechanism of its expression and function in the nervous system