Synthesizing long peptides
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Stepwise elongation, in which the amino acids are connected step-by-step in turn, is ideal for small peptides containing between 2 and 100 amino acid residues. Another method is fragment condensation, in which peptide fragments are coupled. Although the former can elongate the peptide chain without racemization, the yield drops if only it is used in the creation of long or highly polar peptides. Fragment condensation is better than stepwise elongation for synthesizing sophisticated long peptides, but its use must be restricted in order to protect against racemization. Fragment condensation is also undesirable since the coupled fragment must be in gross excess, which may be a limitation depending on the length of the fragment.

A new development for producing longer peptide chains is chemical ligation: unprotected peptide chains react chemoselectively in aqueous solution. A first kinetically controlled product rearranges to form the amide bond. The most common form of native chemical ligation uses a peptide thioester that reacts with a terminal cysteine residue. Other methods applicable for covalently linking polypeptides in aqueous solution include the use of split inteins, spontaneous isopeptide bond formation and sortase ligation.

In order to optimize synthesis of long peptides, Zealand Pharma (located in Denmark in Medicon Valley) invented a method for converting a difficult peptide sequence into an easy peptide sequence. The new technology, called SIP-technology, uses ¡°structure-inducing probes¡± (SIP) to facilitate the synthesis of long peptides. The SIP-technology is a small pre-sequence peptide sequence (e.g. Lysine (Lysn); Glutamic Acid (Glun); (LysGlu)n) that is incorporated at the C-terminus of subsequent resin bound peptide to induce an alpha-helix-like structure in the peptide. The SIP technology constrains the parent peptide into a more ordered conformation using intramolecular hydrogen bonds. This allows the peptide structure to stabilize, and the utilized hydrogen bonds reduce the likelihood of aggregation and degradation by enzymes. In this way, the SIP technology is designed to optimize peptide synthesis, increase biological half-life, improve peptide stability and inhibit enzymatic degradation without altering pharmacological activity or profile of action.