Nerve Regeneration: Cyclopeptides Imitate The Structure And Effect Of The HNK-1

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Nerve Regeneration: Cyclopeptides Imitate The Structure And Effect Of

The HNK-1 Carbohydrate

http://www.medicalnewstoday.com/medicalnews.php?newsid=51966

Carbohydrates play an important role in a broad spectrum of

physiological as well as pathological processes. For example,

polysaccharides on the surface of tumor cells or pathogens are

possible points of attack for therapeutic drugs or vaccinations.

However, the synthesis of carbohydrate-based drugs or vaccines has

proven to be very complex. In addition, these are not easily absorbed

into the body and decompose far too quickly.

Cyclopeptides (short ring-shaped protein chains) called

glycomimetics, which imitate polysaccharides in form and consequently

in function, could be a useful alternative. They are easy to produce,

relatively stable, and easily absorbed.

A team of researchers at the Universities of Bielefeld and Hamburg

(Germany) has now produced cyclopeptides that imitate the HNK-1

carbohydrate from human natural killer cells. HNK-1 is involved in

many developmental biological processes of the nervous system. It

boosts motor neuron axon growth, the growth of the fibers of muscle

nerve cells. HNK-1 is found along the routes used by nerve fibers

after an injury to peripheral nerves.

As a first step, the researchers led by Norbert Sewald (Bielefeld)

and Melitta Schachner (Hamburg) combed through a very large number of

linear peptide chains with random amino acid sequences, searching for

peptides that could be recognized by HNK-1 antibodies. Starting with

the sequences of two such peptides, they synthesized a series of

different cyclic hexapeptides. Their trick was to replace one L-amino

acid in each cyclopeptide with its corresponding D-amino acid. L-

amino acids are the form that occurs in nature, D-amino acids are

their mirror image. Whereas a " normal " cyclic hexapeptide is very

flexible, constantly changing its spatial structure, a D-amino acid

component stabilizes one preferred conformation of the ring. The

peptide " presents " its functional groups of atoms in a predictable

three-dimensional arrangement that is further determined by the

position of the D-amino acid. The amino acid L-proline has a similar

stabilizing effect; so cyclic hexapeptides containing this unit were

also tested.

Sewald and his team identified several interesting candidates based

on their tendency to bind to antibodies against HNK-1. They then took

a closer look at a few of these. Trials with motor neuron cell

cultures demonstrated that two of the mimetics tested did indeed

stimulate axon growth. Indeed, they were more effective than the

linear peptide chains the researchers started with. Structural

analyses and computer simulations identified a particular spatial

structure of the cyclopeptides as being crucial to their

effectiveness.

Substances able to support the regeneration of axons after injuries

could be a highly promising starting point for developing a treatment

of patients with spinal cord injuries. These new cyclopeptides could

be a step in the right direction.