The Cysteine S‐Alkylation Reaction as a Synthetic Method to Covalently Modify Peptide Sequences

• Published in: Chemistry : a European journal 2017-01, Vol.23 (2), p.224-233
• Main Authors: Calce, Enrica, De Luca, Stefania
• Format: Article
• Language: English
• Subjects: Alkylation; Amino Acid Sequence; Amino acids; Ammonia - chemistry; Aziridines - chemistry; Catalysis; Chain reactions; Chains; Cysteine; Cysteine - analogs & derivatives; Cysteine - chemical synthesis; cysteine thio-alkylation; Derivatives; Group dynamics; Peptides; Peptides - chemical synthesis; Peptides - chemistry; Sodium - chemistry; solid-phase synthesis; Solid-Phase Synthesis Techniques - methods; solution-phase synthesis; Sulfhydryl Compounds - chemical synthesis; Sulfhydryl Compounds - chemistry; Thiols; unnatural amino acids; Zinc Acetate - chemistry
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201602694

Synthetic methodologies to chemically modify peptide molecules have long been investigated for their impact in the field of chemical biology. They allow the introduction of biochemical probes useful for studying protein functions, for manipulating peptides with therapeutic potential, and for structure–activity relationship investigations. The commonly used approach was the derivatization of an amino acid side chain. In this regard, the cysteine, for its unique reactivity, has been widely employed as the substrate for such modifications. Herein, we report on methodologies developed to modify the cysteine thiol group through the S‐alkylation reaction. Some procedures perform the alkylation of cysteine derivatives, in order to prepare building blocks to be used during the peptide synthesis, whilst some others selectively modify peptide sequences containing a cysteine residue with a free thiol group, both in solution and in the solid phase. Lipidated peptides: An overview of the cysteine S‐alkylation protocols available for introducing selective modification on peptide molecules is reported (see scheme). They are organized into two main strategies: one performing the chemical modification in solution, while the other one performing the reaction on peptide chains anchored on a solid support.