Synthetic Amino Acids for Applications in Peptide Ligation–Desulfurization Chemistry

Abstract

Native chemical ligation is a powerful tool for the convergent assembly of homogeneous peptide and protein targets from unprotected peptide fragments. The method involves the chemoselective coupling of a peptide thioester with a peptide bearing an N-terminal cysteine (Cys) residue and is mediated by the nucleophilic Cys thiol functionality. A widely adopted extension of the technique for the disconnection of protein targets at alanine (Ala) ligation junctions has been the application of post-ligation desulfurization protocols for the mild removal of the Cys thiol moiety. Recently, attention has turned to the construction of synthetic amino acid building blocks bearing suitably positioned b-, g-, or d-thiol ligation auxiliaries with a view to expanding the scope of the ligation-desulfurization manifold. To date, several thiol-derived amino acids have been prepared, greatly increasing the generality and flexibility of chemoselective ligation technologies for the chemical synthesis of diverse protein targets. This review will highlight the current synthetic approaches to these important amino acid building blocks.

Fully Synthetic Granulocyte Colony-Stimulating Factor Enabled by Isonitrile-Mediated Coupling of Large, Side-Chain-Unprotected Peptides

“…21,22c In this vein, we envisioned reliable means dependent on “now conventional” methods 19,23 to provide expedient access to glycosylated 1 and designed N-linked glycoforms such as 3 (Figure 1). We hypothesize that N-linked glycosylation 9,17,18 may impart improved relative stability and solubility as well as decreased potential for aggregation during chemical assembly.…”

“…The later two-step sequence is well-recognized as a powerful strategy within the field. 23 Despite its broad utility, enabling access to numerous protein targets, our preliminary endeavors were thwarted due to a single recalcitrant dethiylation of Cys127 to provide native Ala127 (vide infra). Notably, target subsequence G-CSF 74–174 harbors no internal Cys residues available for its convergent assembly by NCL.…”

Palladium in the Chemical Synthesis and Modification of Proteins

“…[65] In this early study,t he authors used as eries of heterogeneous palladium reagents,i ncluding Pd/C,P d/Ba-SO 4 ,P d/Al 2 O 3 ,a nd PdO under an H 2 atmosphere for the desulfurization step (Scheme 1). [65] Despite the great innovation of this method and it being inspiring for many developments in this area, [66] side reactions such as hydrogenation of tryptophan residues and the loss of peptides because of absorbance on the metal, limit the use of palladium in this reaction. These limitation have led to the development of ah omogeneous desulfurization approach based on ar adical reaction, which has been the method of choice in many examples of synthetic proteins.…”

Sir John Cornforth Memorial Issue

“…The first Cornforth Review, by Lara R. Malins and Richard Payne (The University of Sydney) on synthetic amino acids for applications in peptide ligationdesulfurization chemistry, is published in this issue. [6] Damon Ridley (formerly of The University of Sydney), who worked with Sir John at Sussex, contributes a foreword with narratives and comments on several of Cornforth's publications. [7] Andrew Holmes (the 2015 Cornforth Lecturer at The University of Sydney) and co-workers at The University of Melbourne and Oxford University report a synthesis of highly water-soluble adamantyl phosphoinositide derivatives.…”