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2‐Methoxy‐4‐methylsulfinylbenzyl: A Backbone Amide Safety‐Catch Protecting Group for the Synthesis and Purification of Difficult Peptide Sequences
Author(s) -
ParadísBas Marta,
TullaPuche Judit,
Albericio Fernando
Publication year - 2014
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201403668
Subject(s) - peptide , trifluoroacetic acid , moiety , protecting group , combinatorial chemistry , amide , peptide synthesis , sequence (biology) , chemistry , peptide sequence , stereochemistry , organic chemistry , biochemistry , alkyl , gene
The use of 2‐methoxy‐4‐methylsulfinylbenzyl (Mmsb) as a new backbone amide‐protecting group that acts as a safety‐catch structure is proposed. Mmsb, which is stable during the elongation of the sequence and trifluoroacetic acid‐mediated cleavage from the resin, improves the synthetic process as well as the properties of the quasi‐unprotected peptide. Mmsb offers the possibility of purifying and characterizing complex peptide sequences, and renders the target peptide after NH 4 I/TFA treatment and subsequent ether precipitation to remove the cleaved Mmsb moiety. First, the “difficult peptide” sequence H‐(Ala) 10 ‐NH 2 was selected as a model to optimize the new protecting group strategy. Second, the complex, bioactive Ac‐(RADA) 4 ‐NH 2 sequence was chosen to validate this methodology. The improvements in solid‐phase peptide synthesis combined with the enhanced solubility of the quasi‐unprotected peptides, as compared with standard sequences, made it possible to obtain purified Ac‐(RADA) 4 ‐NH 2 . To extend the scope of the approach, the challenging Aβ(1‐42) peptide was synthesized and purified in a similar manner. The proposed Mmsb strategy opens up the possibility of synthesizing other challenging small proteins.