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Method Article
Erode N Prabhakaran
Indian Institute of Science, Bangalore
Corresponding Author
ORCiD: https://orcid.org/0000-0002-9195-1199
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Short Turn and Helix mimics frequently represent molecular recognition surfaces perturbing bio-relevant protein-biomolecular interfaces. Generic methods that can stabilize short peptides into turns or helices by retaining all recognition elements, have tremendous applications in drug discovery. Here, a versatile modular synthetic protocol is presented for stabilizing turns and helices of different sizes by replacing their ring-closing hydrogen bonds with a generic three-carbon covalent surrogate. Two Fukuyama-Mitsunobu reactions insert the surrogate between desired residues in high yields and purity. Coupling with turn size-dependent oligopeptides containing both sterically restricted and non-coded residues, followed by macrolactamization yield a variety of stabilized turns. Short peptide extensions at the C-terminus of these turns yield stabilized 310-helices and α-helices. This solution-phase synthetic approach provides combinatorial access to libraries of stabilized turns and helices with all their native residues retained, in >100 mmole scales, in about one week per stabilized mimic, to technicians with postgraduate level training.
Keywords
α-helix, Hydrogen Bond Surrogate, Fukuyama-Mitsunobu reaction, solution-phase synthesis, Peptides, Cyclization
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Chemical biology
An open repository of community-contributed protocols sponsored by Nature Research.
Learn more about Protocol Exchange
Method Article
Erode N Prabhakaran
Indian Institute of Science, Bangalore
Corresponding Author
ORCiD: https://orcid.org/0000-0002-9195-1199
Version History
CURRENT STATUS: Posted
Version 1
Posted 26 May, 2021
No community comments so far
Metrics
Comments: 0
HTML Views: ...
Subject Areas
Chemical biology
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Short Turn and Helix mimics frequently represent molecular recognition surfaces perturbing bio-relevant protein-biomolecular interfaces. Generic methods that can stabilize short peptides into turns or helices by retaining all recognition elements, have tremendous applications in drug discovery. Here, a versatile modular synthetic protocol is presented for stabilizing turns and helices of different sizes by replacing their ring-closing hydrogen bonds with a generic three-carbon covalent surrogate. Two Fukuyama-Mitsunobu reactions insert the surrogate between desired residues in high yields and purity. Coupling with turn size-dependent oligopeptides containing both sterically restricted and non-coded residues, followed by macrolactamization yield a variety of stabilized turns. Short peptide extensions at the C-terminus of these turns yield stabilized 310-helices and α-helices. This solution-phase synthetic approach provides combinatorial access to libraries of stabilized turns and helices with all their native residues retained, in >100 mmole scales, in about one week per stabilized mimic, to technicians with postgraduate level training.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
This is a list of supplementary files associated with this preprint. Click to download.
- Tables.pdf
Tables
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