Recent departures in the synthesis of peptides and glycopeptides

Abstract

In this account, we describe the results of a research program directed to the proposition that chemical synthesis can play a valuable role in identifying biologic level molecules worthy of pharma level development. We recount our journey towards the chemical synthesis of homogeneous erythropoietin, the challenges we encountered, and our efforts to address deficiencies in the current "state of the art" of glycopeptide synthesis. Here we describe new methods for the synthesis of glycopeptides that have emerged from the erythropoietin adventure, including the development of unique C-terminal acyl donors, novel amide bond forming methods, and new ligation and coupling strategies.

Probing the stability of nonglycosylated wild-type erythropoietin protein via reiterative alanine ligations

“…The fourth fragment, peptide 11 (shown in Scheme 5), was prepared by treatment of the resinbound protected peptide with Cocktail B. The four fragments (8)(9)(10)(11) were sequentially merged through a series of iterative NCL/thiazolidine removal sequences (Scheme 5). Thus, peptide 11, possessing an N-terminal cysteine residue, and peptide 10, bearing a latent C-terminal thioester, were combined in phosphate buffer solution containing guanidine•HCl, TCEP•HCl, and MPAA at pH 7.2-7.4.…”

Total Synthesis of Glycosylated Proteins

“…To address this issue, our group has been engaged in the development of a number of synthetic strategies that may have broad utility for the preparation of homogeneously glycosylated peptides and proteins [44, 45]. In pursuing modified NCL strategies, we and others have sought to replace the labile C-terminal thioester with more stable latent thioester or alternative acyl donor groups.…”

Die Wissenschaft von Proteinen im Reich der organischen Chemie begründen: Totalsynthese von SEP (synthetisches Erythropoeseprotein)

“…Aus diesen Arbeiten werden sich nützliche Anwendungen der organischen Synthesechemie für die Herstellung von EPO-Glycoformen mit definierter Struktur und biologischen Eigenschaften ergeben: "de novo chemical synthesis might provide a powerful path to designed glycoproteins as it offers, in principle, precise structural control while providing opportunities for systematic variation of both the structures of the glycodomains and their location within the peptide sequence." [50] Durch das Design und die chemische Totalsynthese von SEP wird ein Weg zu systematisch abgestimmten Eigenschaften von EPO und anderen Glycoproteinen geebnet. …”