Abstract
Polyproline sequences are highly abundant in prokaryotic and eukaryotic proteins, where they serve as key components of secondary structure. To date, construction of the proline-proline motif has not been possible owing to steric congestion at the ligation junction, together with an n → π* electronic interaction that reduces the reactivity of acylated proline residues at the C-terminus of peptides. Here, we harness the enhanced reactivity of prolyl selenoesters and a trans-γ-selenoproline moiety to access the elusive proline-proline junction for the first time through a diselenide-selenoester ligation-deselenization manifold. The efficient nature of this chemistry is highlighted in the high-yielding one-pot assembly of two proline-rich polypeptide targets, submaxillary gland androgen regulated protein 3B and lumbricin-1. This method provides access to the most challenging of ligation junctions, thus enabling the construction of previously intractable peptide and protein targets of increasing structural complexity.
Highlights
Peptide ligation chemistry has revolutionized protein science by providing a means to access large polypeptide and protein targets,[1−3] including those that cannot be generated by recombinant expression technologies
Information), but as reported for other diselenide building blocks,[12] we observed that only one-half of the diselenide amino acid was able to couple to a resin-bound peptide chain
Having established that the γ-selenoproline moiety is competent in additive-free Diselenide−Selenoester Ligation (DSL)−deselenization chemistry, we investigated whether the method could be expanded to include C-terminal Pro selenoesters in an attempt to forge previously intractable Pro−Pro junctions
Summary
Peptide ligation chemistry has revolutionized protein science by providing a means to access large polypeptide and protein targets,[1−3] including those that cannot be generated by recombinant expression technologies. Having established that the γ-selenoproline moiety is competent in additive-free DSL−deselenization chemistry, we investigated whether the method could be expanded to include C-terminal Pro selenoesters in an attempt to forge previously intractable Pro−Pro junctions. The additive-free DSL reaction between 22 and 9 proceeded to completion within 16 h, and, following in situ deselenization and purification by HPLC, peptide product 23 was isolated in 55% yield (Scheme 3A).
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