Bio-orthogonal chemistry methodologies and chemical biology of cysteine redox signalling

Abstract

There is an extensive library of post translational modifications (PTMs) that occur naturally within cells and across diverse organisms, and each can lead to remarkable changes in protein properties and function. Many PTMs are reversible and hence are useful in cell regulation and signalling. Cysteine sulfinic acid (CSA) was thought to be an irreversible modification of cysteine until the discovery of sulfiredoxin (Srx) in 2003 and is now thought to have a possible role in the redox regulation of cells. Very little is known about the redox biology and stability of CSA making this an area of key interest. To be able to learn more about CSA, new methodologies to incorporate this amino acid selectively into a wide variety of peptides was required. Here we describe the development of new methodologies for the synthesis of sulfinylated peptides including the design of the CSA protecting group. CSA was incorporated into peptides using standard Fmoc solid phase peptide synthesis via the pyrimidine protected ‘Fmoc CSA precursor’ synthesised enantiopure on multigram scale (preliminary results suggest that the product is enantiopure, but further analysis is required to confirm initial results). A library of sulfinylated peptides were synthesised and their identities confirmed by HR-MS and purity by HPLC. Model CSA derivatives were used to begin to investigate the properties and stability of the CSA functional group in vitro using analytical methods such as quantitative NMR and MS. The development of compounds that incorporate CSA, paves the way towards future studies which would allow a greater understanding into the role of CSA in proteins and redox regulation.

More information

Identifiers

ORCID for Laura Jane Hayward: orcid.org/0000-0003-2636-1392

ORCID for Matthias Baud: orcid.org/0000-0003-3714-4350

ORCID for Sam Thompson: orcid.org/0000-0001-6267-5693

Catalogue record

Export record