In order to induce structural conformation in peptides many scientists have utilized cyclization due to the versatile methods of peptide synthesis and availability of protecting groups which can be orthogonally removed. Constrained peptides have been shown to have improved the biological properties compared to the linear peptides.

1. Applications of Constrained Peptides to Various Biological Processes
Eunice Murage, Ph.D. and Miguel Castro, Ph.D.
Protein Chemistry, Bio-Synthesis, Inc., Lewisville, Texas 75057
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Introduction H H
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In order to induce structural conformation in peptides many scientists H N
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have utilized cyclization due to the versatile methods of peptide synthesis
Hydrocarbon stapling using Lactam bridge formation
and availability of protecting groups which can be orthogonally removed. ring closing metathesis
Constrained peptides have been shown to have improved the biological NH
Backbone
properties compared to the linear peptides. Cyclization
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For example, cyclic peptides have shown:
1. Enhanced receptor affinity and efficacy O
2. Improved cell permeability and enzyme stability R5
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In addition, these constraints provide a conceptual approach towards Li HN O
designing of peptidomimetics.
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Classic Examples
Hydrocarbon Stapled Peptides
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Lactam Bridge Peptides
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Peptide Type of Modification Properties
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α - Conotoxin N- to C- terminus cyclization Increased stability in human plasma1 O
Hydrocarbon stapling Increased protease resistance
BID BH3 Head to tail/ end to side chain cyclization
using ring closing metathesis and serum stability2
Hydrocarbon stapling Increase binding affinity towards Conclusion:
NOTCH1
using ring closing metathesis NOTCH transactivation complex3
It is scientifically evidenced that constrained peptides in form of stapled or lactam-bridged
DP178 Side chain to side chain i, Increase HIV inhibitory activity as a
have attractive biological properties superior to their linear counterparts and introduced a
(HIV35) i+7 lactam bridge formation result of stabilized α-helical conformation4
unique technique for studying protein-protein interactions which mediates most of biological
actions.
In order to further study peptides with these promising properties, BIOSYNTHESIS, INC. has
recently launched a peptide conformation screening tool called positional cyclization
Acknowledgement:
scanning.
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I would like to thank Ian Flynn and Heidi Fazeli and for design and support. This technique is aimed at identifying the receptor-bound conformation of various biological
References: peptides by constraining specific segment of the peptide
and studying its effect on the biological
1. Clark et al. Proc Natl Acad Sci USA 2005, 102, 13767–13772. activity.
2. Walensky et. al., Science, 2004, 3, 1466-1470
3. Raymond et. al., Nature 2009, 462, 182-188.
4. Judice et. al., Proc. Natl. Acad. Sci. USA. 1997, 94, 13426-13430
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