Miklós Bodanszky Award Lecture: Selective chalcogen chemistry to study protein science

Abstract

In recent decades, chemical protein synthesis and the development of chemoselective reactions—including ligation reactions—have led to significant breakthroughs in protein science. Among them are a better understanding of protein structure‐function relationships, the study of protein posttranslational modifications, exploration of protein design, unnatural amino acid incorporation, and the study of therapeutic proteins and protein folding. Chalcogen chemistry, especially that of sulfur and selenium, is quite rich, and we have witnessed continuous progress in this field in recent years. In this short review, we will instead summarize three stories that we have recently presented on chalcogen chemistry and its impact on protein science, which was presented in the Miklós Bodanszky Award Lecture at the 35th European Peptide Society Meeting in Dublin, Ireland, 26 August 2018.

Chemical synthesis of per‐selenocysteine human epidermal growth factor

“…Among them, the substitution of the cysteine residues of a disulfide bond with selenocysteine (Sec) with its very negative redox potential 2,3 leads to a very fast preferential diselenide bond formation even in presence of additional cysteine residues. In addition, the diselenide substitution is very promising due to the almost isomorphous replacement of disulfides in terms of structure and function, 4–10 as first reported by Pegoraro et al in the case of endothelin 11 . Alewood and co‐workers reported diselenide‐substituted conotoxin, in which the biological activity is similar, and it showed higher stability to plasma and glutathione compared to the native one 12,13 .…”

“…As a diselenide bond is very quickly formed compared to the disulfide bond, it was found that if one of the disulfide bonds is substituted with diselenide bond, it induces correct oxidative folding by its preferential and quick formation of productive intermediate leading to the desired final product 4–10 . The introduction of diselenide bond at the non‐native position can steer the fast production of the native pairing via the less stable intermediate 16,17 .…”

“…substituted with diselenide bond, it induces correct oxidative folding by its preferential and quick formation of productive intermediate leading to the desired final product. [4][5][6][7][8][9][10] The introduction of diselenide bond at the non-native position can steer the fast production of the native pairing via the less stable intermediate. 16,17 On the other hand, the folding upon replacing all four cysteines with selenocysteine in α-conotoxin ImI was found to occur in a similar manner to the native cysteine peptide leading to the mixture of globular isomer and the ribbon isomer.…”