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

Florent Kerdraon,Oleg Melnyk,Gemma Bogard,Vangelis Agouridas,Muriel Pichavant,Benoît Snella,Hervé Drobecq

doi:10.3390/molecules26051386

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.

Highlights

IntroductionOne corpus of methods that has contributed to the progress of chemical protein synthesis exploits the capacity of N-(2-mercaptoethyl)amides, i.e., N,S-acyl shift systems [18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36], to rearrange into thioesters in aqueous media
Thioester chemistry is central to the field of chemical protein synthesis by the frequent application of the native chemical ligation (NCL [2,3,4,5,6], Figure 1A) and desulfurization methods [7,8,9,10] to the chemoselective formation of peptide junctions to cysteine or alanine in water using unprotected peptide segments as reactants [11]
Besides the assembly of the protein itself and the acceleration of peptide bond formation [12,13,14,15,16], one limitation of chemical protein synthesis using NCL is the production of the peptide thioester segments [17]

Summary

Introduction

One corpus of methods that has contributed to the progress of chemical protein synthesis exploits the capacity of N-(2-mercaptoethyl)amides, i.e., N,S-acyl shift systems [18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36], to rearrange into thioesters in aqueous media. Several of these systems have been validated by the synthesis of challenging proteins [37,38,39,40,41,42,43,44]

Methods

Results

Conclusion