Dithiol amino acids can structurally shape and enhance the ligand-binding properties of polypeptides

From:http://www.nature.com/nchem/journal/v6/n11/full/nchem.2043.html

Shiyu Chen,RanganathGopalakrishnan, Tifany Schaer,FabriceMarger, Ruud Hovius,DanielBertrand, FlorencePojer & Christian  Heinis

Nature Chemistry6,1009–1016(2014)doi:10.1038/nchem.2043

Abstract

The disulfide bonds that form between two ​cysteine residues are important in defining and rigidifying the structuresof proteins and peptides. In polypeptides containing multiple ​cysteine residues, disulfide isomerization can lead to multiple productswith different biological activities. Here, we describe the development of adithiol amino acid (Dtaa) that can form two disulfide bridges at a single aminoacid site. Application of Dtaas to a serine protease inhibitor and a nicotinicacetylcholine receptor inhibitor that contain disulfide constraints enhancedtheir inhibitory activities 40- and 7.6-fold, respectively. X-raycrystallographic and NMR structure analysis show that the peptide ligandscontaining Dtaas have retained their native tertiary structures. We furthermoreshow that replacement of two ​cysteines by Dtaas can avoid the formation of disulfide bond isomers. Withthese properties, Dtaas are likely to have broad application in the rationaldesign or directed evolution of peptides and proteins with high activity andstability.