Oxidative Protein Folding With Small Molecules

The in vitro oxidative folding of disulfide containing proteins has traditionally been enhanced by the addition of redox active small molecules, usually aliphatic thiols such as glutathione. Although enhanced, in many cases folding is still kinetically slow and/or low yielding. In response to the need for improved folding, additional types of redox active small molecules have recently been examined, such as bis(cysteine) containing peptides, small molecule dithiols, aromatic thiols, and selenols. In general, these molecules have demonstrated the ability to improve either or both protein folding rates and yields compared to the standard reagent glutathione, although only a limited number of proteins have been examined so far. Some promising results have also been obtained with in vivo folding. Herein, the evidence in support of each type of molecule is presented and discussed, and some general conclusions are presented. Ultimately, the field is likely to undergo both expansion and consolidation as more examples are investigated.