Solid-Phase Synthesis of an “Inaccessible” hGH-Derived Peptide Using a Pseudoproline Monomer and SIT-Protection for Cysteine

Published on 05/09/2022

Herein, we report the first-time SPPS of a special peptide sequence via employment of of a serine pseudoproline building block as well as sec-isamyl mercaptan (SIT) as cysteine protecting group.

Srinivasa Rao Manne, Amit Chakraborty, Karin Rustler, Thomas Bruckdorfer, Beatriz G. de la Torre, and Fernando Albericio

ACS Omega 2022, 7, 32, 28487–2849

Abstract: The solid-phase peptide synthesis (SPPS) of the C-terminal sequence of hGH with one extra Tyr attached to its N-terminus (total of 16 residues with a disulfide bridge) has been accomplished for the first time by optimizing several synthetic parameters. First of all, the two Ser residues (positions 9 and 13 of the molecule) have been introduced as a single amino acid, Fmoc-Ser(ψMe,Mepro)-OH, demonstrating that the acylation of these hindered moieties is possible. This allows us to avoid the use of the corresponding dipeptides, Fmoc-AA-Ser(ψMe,Mepro)-OH, which are very often not commercially available or very costly. The second part of the sequence has been elongated via a double coupling approach using two of the most effective coupling methods (DIC-OxymaPure and HATU-DIEA). Finally, the disulfide bridging has been carried out very smoothly by a chemoselective thiol-disulfide interchange reaction between a SIT (sec-isoamyl mercaptan)-protected Cys residue and the free thiol of the second Cys. The synthesis of this short peptide has evidenced that SPPS is a multifactorial process which should be optimized in each case.