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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 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.

R1

Properties

α - Conotoxin

N- to C- terminus cyclization

Increased stability in human plasma1

BID BH3

Hydrocarbon stapling using ring closing metathesis

Increased protease resistance and serum stability2

NOTCH1

Hydrocarbon stapling using ring closing metathesis

Increase binding affinity towards NOTCH transactivation complex3

Side chain to side chain i, i+7 lactam bridge formation

Increase HIV inhibitory activity as a result of stabilized α-helical conformation4

DP178 (HIV35)

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Acknowledgement:

I would like to thank Ian Flynn and Heidi Fazeli and for design and support.

References: 1. 2. 3. 4.

Clark et al. Proc Natl Acad Sci USA 2005, 102, 13767–13772. Walensky et. al., Science, 2004, 3, 1466-1470 Raymond et. al., Nature 2009, 462, 182-188. Judice et. al., Proc. Natl. Acad. Sci. USA. 1997, 94, 13426-13430

www.biosyn.com Service across Genomics, Proteomics and Cell Biology

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Lactam bridge formation

NH O

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Hydrocarbon Stapled Peptides

Type of Modification

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Backbone Cyclization

In addition, these constraints provide a conceptual approach towards designing of peptidomimetics.

Peptide

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Hydrocarbon stapling using ring closing metathesis

For example, cyclic peptides have shown: 1. Enhanced receptor affinity and efficacy 2. Improved cell permeability and enzyme stability

Classic Examples

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R1

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NH R2

Li

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H N

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HN HN

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Lactam Bridge Peptides

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Head to tail/ end to side chain cyclization

Conclusion: It is scientifically evidenced that constrained peptides in form of stapled or lactam-bridged have attractive biological properties superior to their linear counterparts and introduced a 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 scanning. This technique is aimed at identifying the receptor-bound conformation of various biological peptides by constraining specific segment of the peptide and studying its effect on the biological activity.

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Applications of Constrained Peptides to Various Biological Processes