Dataset Information

Ketoxime peptide ligations: oxidative couplings of alkoxyamines to N-aryl peptides.

ABSTRACT: Chemoselective ligation methods that preserve or introduce side chain diversity are critical for chemical synthesis of peptides and proteins. Starting from ketone substrates instead of aldehydes in oxime ligation reactions would allow substitution at the site of ligation; however, synthetic challenges to readily access ketone derivatives from common amino acid building blocks have precluded the widespread use of ketoxime peptide ligation reactions thus far. Moreover, ketones are typically much slower to react in condensation reactions compared to aldehydes. Here, one-pot catalyst-free oxidative couplings of ?-substituted N-aryl peptides with alkoxyamines provide access to oxime linkages with diverse side chains. Electron-rich N-(p-Me2N-phenyl)-amino acids possessing substituents at the ?-carbon were found to be uniquely capable of undergoing site-selective ?-C-H oxidations in situ under an O2 atmosphere at neutral pH. Comparative studies with N-arylglycinyl peptides revealed that substitution at the ?-carbon caused notable changes in reactivity, with greater sensitivity to solvent and buffer salt composition.

SUBMITTER: Guthrie QAE

PROVIDER: S-EPMC7017874 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Ketoxime peptide ligations: oxidative couplings of alkoxyamines to <i>N</i>-aryl peptides.

Guthrie Quibria A E QAE Young Hailey A HA Proulx Caroline C

Chemical science 20190829 41

Chemoselective ligation methods that preserve or introduce side chain diversity are critical for chemical synthesis of peptides and proteins. Starting from ketone substrates instead of aldehydes in oxime ligation reactions would allow substitution at the site of ligation; however, synthetic challenges to readily access ketone derivatives from common amino acid building blocks have precluded the widespread use of ketoxime peptide ligation reactions thus far. Moreover, ketones are typically much s ...[more]

PMID: 32110307

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Project description:Disulfide bridges in proteins are formed by the oxidation of pairs of cysteine residues. These cross-links play a critical role in stabilizing the 3D-structure of small disulfide rich polypeptides such as hormones and venom toxins. The arrangement of the multiple disulfide bonds directs the peptide fold into distinct structural motifs that have evolved for resistance against biochemical and physical insults. These structural scaffolds have, therefore, proven to be very attractive in bioengineering efforts to develop novel biologics with applications in health and agriculture. Structural characterization of small disulfide rich peptides (DRPs) presents unique challenges when using commonly applied biophysical methods. NMR is the most commonly used method for studying such molecules, where the relatively small size of these molecules results in highly precise structural ensembles defined by a large number of distance and dihedral angle restraints per amino acid. However, in NMR the sulfur atoms that are involved in three of the five dihedral angles in a disulfide bond cannot be readily measured. Given the central role of disulfide bonds in the structure of these molecules, it is unclear what the inherent resolution of such NMR structures is when using traditional NMR methods. Here, we use an extensive set of long-range residual dipolar couplings (RDCs) to assess the resolution of the NMR structure of a disulfide-rich peptide. We find that structures based primarily on NOEs, yield ensembles that are equivalent to a crystallographic resolution of 2-3 Å in resolution, and that incorporation of RDCs reduces this to ~1-1.5 Å resolution. At this resolution the sidechain of ordered amino acids can be defined accurately, allowing the geometry of the cysteine bridges to be better defined, and allowing for disulfide-bond connectivities to be determined with high confidence. The observed improvements in resolution when using RDCs is remarkable considering the small size of these peptides.

Dataset Information

Ketoxime peptide ligations: oxidative couplings of alkoxyamines to N-aryl peptides.

Publications

Ketoxime peptide ligations: oxidative couplings of alkoxyamines to <i>N</i>-aryl peptides.

Similar Datasets

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