Insights into the Mechanism and Catalysis of Peptide Thioester Synthesis by Alkylselenols Provide a New Tool for Chemical Protein Synthesis

Abstract

While thiol-based catalysts are widely employed for chemical protein synthesis relying on peptide thioester chemistry, this is less true for selenol-based catalysts whose development is in its infancy. In this study, we compared different selenols derived from the selenocysteamine scaffold for their capacity to promote thiol–thioester exchanges in water at mildly acidic pH and the production of peptide thioesters from bis(2-sulfanylethyl)amido (SEA) peptides. The usefulness of a selected selenol compound is illustrated by the total synthesis of a biologically active human chemotactic protein, which plays an important role in innate and adaptive immunity.

Design of Novel Alkylselenol Catalysts Enabling Peptide Thioester and Protein Chemical Synthesis

“…Although the selenol group also presents interesting properties in this regard, selenol-based catalysts have been largely overlooked. In this study, we designed various selenocysteamine-derived alkyl selenols in the form of the corresponding diselenide precursors 1-3 (Figure 1a) and assessed their capacity to promote the formation of thioesters from bis(2-sulfanylethyl)amido (SEA) peptides 4 (Figure 1b) [3,4]. The more promising candidate was then used to prepare granulysin (9-GN), a 9 kDa human protein involved in immunity.…”

Synthesis and Applications of Organic Selenols

“…Densely functionalised organoselenium compounds, bearing labile groups and characterised by high molecular complexity, can be prepared exploiting the reactivity of selenols. Selenols are also employed as catalysts for the synthesis of peptide thioesters or peptide ligation from bis(2-sulfanylethyl)amido (SEA) peptides [12][13] Catalytic amounts of selenols were demonstrated to have a beneficial effect on the chain propagation step of the radical fragmentation of βlactones, thus enabling to improve the efficiency of the process. [14] On the other hand, investigating the chemical behaviour of suitably substituted stabilised selenols is of paramount importance in order to elucidate the mechanism of selenoenzymes.…”