A major problem in the synthesis of long peptides (>50 AAs) is poor solvation during assembly of the protected peptide. The situation is exacerbated in very long sequences as coupling and deprotection reactions are prevented from proceeding to completion. This phenomenom can also occur in short peptides with so-called difficult sequences, where the protected peptide derivatives associate into stable secondary structures such as beta-sheet like structures [Houben-Weyl, Methods in Organic Chemistry, Volume E22, Synthesis of Peptides and Peptidomimetics, Thieme Medical Publishers, 4th edition, 2002].
The key to the successful synthesis of long peptides is to overcome the aforementioned aggregation problems. For that, a variety of strategies have been described in the literature. Examples are the use of
- High-swelling resins with low peptide loadings
- Special solvent mixtures (magic mixtures, chaotropic salts)
- Increased temperatures, including microwave
- Solubilizing protecting groups
- Pseudoproline building blocks
- Fragment condensation
- Native chemical ligation (NCL)
- Other condensations
After careful evaluation of the target peptide sequence, JPT scientists chose the most promising synthetic strategy employing well documented protocols to ensure a high success-rate. Over the past two decades, JPT has amassed considerable experience in the successful synthesis of hundreds of difficult, highly challenging long peptides, with lengths of up to100 amino acids.
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