I am now doing the solid-phase peptide synthesis of the GnRH antagonist, ozarelix. Here are the amino acid sequences of it: Ac-D-2Nal-D-Phe(4-Cl)-D-3Pal-Ser-N(Me)Tyr-D-hCit-Nle-Arg-Pro-D-Ala-NH2.
The question is that I used an automated peptide synthesiser and it showed I need to couple Fmoc-Arg(Pbf)-OH twice. I have read some articles about Arginine in SPPS and they said it is due to the bulky side chain and corresponding protecting group.
I am confused about how the side chain and Pbf protecting group affect the coupling step. And why it should be coupled twice?
Bulkiness is one of the reasons but when activated, Arg often undergoes a crucial side-reaction too. Once the carboxylic group of the protected Arg is activated, a stable six-member δ-lactam formation takes place, which inhibit the incorporation of Arg into the growing peptide sequence. Most of the time this side-reaction does not modify the final peptide, but for long peptides often leads to the formation of deletion/truncated peptides, with missing Arg residue. To minimize this issue repetitive couplings of protected Arg are often carried out.
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