Abstract
Protecting group chemistry for the cysteine thiol group has enabled a vast array of peptide and protein chemistry over the last several decades. Increasingly sophisticated strategies for the protection, and subsequent deprotection, of cysteine have been developed, facilitating synthesis of complex disulfide-rich peptides, semisynthesis of proteins, and peptide/protein labelling in vitro and in vivo. In this review, we analyse and discuss the 60+ individual protecting groups reported for cysteine, highlighting their applications in peptide synthesis and protein science.
Highlights
The concept of protecting, and subsequently deprotecting, functional groups is of paramount importance in synthetic chemistry.[1,2,3] Protecting group strategies in particular feature extensively in the synthesis of peptides, whereby amino acid building blocks are coupled to one another via amide bonds
Peptide fragments for native chemical ligation (NCL) can be synthesised chemically via solid phase peptide synthesis (SPPS) or, when significantly longer peptide fragments are desired, can be produced recombinantly in bacterial expression systems such as in Escherichia coli (E. coli) cells. These recombinantly produced peptides contain an intein segment fused to the C-terminus, which can undergo N,S-acyl shift and, following addition of an exogenous thiol such as sodium 2-mercaptoethanesulfonate (MESNa), cleavage to yield a thioester-containing peptide fragment that can subsequently participate in NCL; this process is known as expressed protein ligation (EPL, Fig. 3b).[40,41]
Methods for the protection, and subsequent deprotection, of the thiol side chain of Cys has enabled a vast array of peptide and protein chemistry over the last 70 years
Summary
The concept of protecting, and subsequently deprotecting, functional groups is of paramount importance in synthetic chemistry.[1,2,3] Protecting group strategies in particular feature extensively in the synthesis of peptides, whereby amino acid building blocks are coupled to one another via amide bonds. Clıona McMahon obtained her MSci degree in Natural Sciences at UCL, majoring in synthetic organic chemistry and minoring in cell and molecular biology Her master’s research project focused on the development of a cysteine protecting group for use in solid phase peptide synthesis. She will begin a PhD in Chemical Biology in September 2021 in the Chudasama Group, working in the areas of protein and peptide modification. For each group (and where applicable), this review will focus on (a) the conditions used for its deprotection, (b) use in Boc and Fmoc peptide synthesis, (c) its comparison to other related Cys protecting groups, and (d) notable applications of the Cys protecting group in peptide and protein chemistry
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