Methionine sulfoxide- and sulfone-containing peptide synthesis: management of a relevant post-translational modification in proteins

Methionine (Met) is with Cysteine one of the most easily oxidized amino acids. Sulfoxide and sulfone forms can both be formed, only the latter being irreversible in biological systems, with important consequences on protein interactions and structuration. In this paper we discuss the conditions for Met oxidation in solid-phase peptide synthesis (SPPS). As case studies we selected the following peptide sequences: the biologically relevant β-amyloid (1-40) in which Met oxidation could decrease the aggregation and toxicity in Alzheimer’s disease and an irrelevant tetradecapeptide GHSVFLAPYGWMVK. In particular we investigated manual and classical in batch or microwave-assisted automatic SPPS (MW-SPPS) to evaluate the synthetic conditions to obtain Met oxidation and we highlighted the experimental parameters for automated MW-SPPS. Moreover, we reported specific conditions to deal with sulfoxide formation just in case non-oxidized Met-containing peptides have to be obtained.