Custom Stapled Peptide Synthesis

Stapled-Peptide synthesis

Stapled peptide is a new type of peptide with hydrocarbon-stapled α-helix peptides. Compared with natural peptides, stapled peptides have higher enzymatic hydrolysis stability and can penetrate the cell membrane, thus improving its pharmacological properties. Due to these significant advantages, stapled peptides have become an important structural modification method for active peptides, which will lead to the formation of more novel peptide drugs targeting protein-protein interactions(PPI).

 

Protein-protein interaction plays an important role in many biological processes, such as virus self-assembly, cell proliferation, growth, differentiation and programmed death.Many potential therapeutic targets in human diseases are mainly protein-protein interactions.Because most PPI surfaces are large and discontinuous, it is difficult for small molecule reagents to bind closely to them.The biggest disadvantage of protein drugs is their inability to penetrate cell membranes and then target the interior of cells.

 

Through long-term accumulation of experiments, Omizzur peptide has continuously optimized the peptide synthesis conditions and purification process, and has possessed mature synthesis process of stapled peptides. Omizzur has been proved to have the ability to provide high-quality stapled peptides to the world, to fully meet various R & D needs of customers.


                                                                       Comparison of three kinds of pharmaceutics molecules


Object

Molecular weight (Da)

AdvantagesDisadvantages
Small organic molecules<1000

1. High stability

2. high cellular permeability

3. Low cost of production

1. Severe side effects

2. Inability to disrupt protein-protein interaction

Protein>10000

1. Low toxicity

2. Ability to selectively target protein interfaces

3 .Having large shallow surfaces

1. Poor in vivo stability

2. Unable to traverse cell membranes

3 .High cost of production

Stapled peptides1000-5000

1. Low toxicity

2. High stability in vivo

3. Accessible to target intracellular proteins with specificity

Need more research for safety and efficacy in human

Studies have found that peptides with alpha helical structure and rich positive charges can cross the cell membrane, however, once the peptides are separated from the matrix, they cannot maintain the original secondary structure.Using carbon-carbon bonds as scaffolds can stabilize the peptide alpha helical structure.The peptide obtained by this method is called stapled peptide.The stapled peptide has a higher degree of alpha helix, with a 5-5,000-fold increase in binding capacity to the target. In addition, stapled peptides can penetrate cell membranes, and difficult to be hydrolyzed by proteases, then have a long half-life in organisms.

 

The synthesis strategy of stapling peptide is: firstly, two α- methyl, α- alkenyl unnatural amino acids are accessed into the solid-phase synthesis of peptide chain, and then the stapling peptide is obtained by RCM reaction. In recent years, stapled peptide have made progress in the treatment of cancer, the inhibition of AIDS and hepatitis C and the regulation of signaling pathways.


References

1.Villoutreix BO, Labbe CM, Lagorce D, et al.   A leap into the chemical  space  of  protein-protein  interaction  inhibitors  [J].  Curr Pharm Des, 2012, 18: 4648−4667.

2.Cromm PM, Spiegel J, Grossmann TN.   Hydrocarbon stapled peptides as modulators of biological function [J].   ACS Chem Biol, 2015, 10: 1362−1375.

3.Phillips C, Roberts LR, Schade M, et al.  Design and structure of  stapled  peptides  binding  to  estrogen  receptors  [J]. J Am Chem Soc, 2011, 133: 9696−9699

4.Speltz TE, Fanning SW, Mayne CG, et al. Stapled peptides with γ-methylated hydrocarbon chains for the estrogen receptor/ coactivator interaction [J].  Angew  Chem  Int  Ed  Engl,  2016, 55: 4252−4255。

5.Bird GH, Boyapalle S, Wong T, et al.   Mucosal delivery of a double-stapled RSV peptide prevents nasopulmonary infection [J]. J Clin Invest, 2014, 124: 2113−2124