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Peptide backbone amide substitution can dramatically alter the conformational and physiochemical properties of native sequences. Although uncommon relative to N -alkyl substituents, peptides harboring main-chain N -hydroxy groups exhibit unique conformational preferences and biological activities. Here, we describe a versatile method to prepare N -hydroxy peptide on solid support and evaluate the impact of backbone N -hydroxylation on secondary structure stability. Based on previous work demonstrating the β-sheet-stabilizing effect of α-hydrazino acids, we carried out an analogous study with N -hydroxy-α-amino acids using a model β-hairpin fold. In contrast to N -methyl substituents, backbone N -hydroxy groups are accommodated in the β-strand region of the hairpin without energetic penalty. An enhancement in β-hairpin stability was observed for a di- N -hydroxylated variant. Our results facilitate access to this class of peptide derivatives and inform the use of backbone N -hydroxylation as a tool in the design of constrained peptidomimetics.
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Synthesis and conformation o fbackbone N-aminated peptides
The chemical modification of peptides is a promising approach for the design of protein-protein interaction inhibitors and peptide-based drug candidates. Among several peptidomimetic strategies, substitution of the amide backbone maintains side-chain functionality that may be important for engagement of biological targets. Backbone amide substitution has been largely limited to N-alkylation, which can promote cis amide geometry and disrupt important H-bonding interactions. In contrast, N-amination of peptides induces distinct backbone geometries and maintains H-bond donor capacity. In this chapter we discuss the conformational characteristics of designed N-amino peptides and present a detailed protocol for their synthesis on solid support. The described methods allow for backbone N-amino scanning of biologically active parent sequences.
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- Award ID(s):
- 2021265
- PAR ID:
- 10303791
- Date Published:
- Journal Name:
- Methods in enzymology
- Volume:
- 656
- ISSN:
- 1557-7988
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1016/bs.mie.2021.04.013
