Synthesis of Cyclic Peptides containing Unnatural Amino Acids

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Cyclic peptides play an important role in pharmaceuticals by offering enhanced stability and improved bioavailability compared to linear peptides whilst maintaining precise target specificity. This allows them to effectively target various disease pathways with minimized off-target effects.

The integration of unnatural amino acids into pharmaceutical (cyclic)peptides not only further enhances stability, target specificity and bioavailability, but can also help mitigate immunogenicity. However, incorporating unnatural amino acids into peptides can be challenging due to their synthetic complexity, stereochemistry intricacies, and compatibility issues with standard peptide protocols. 

At Charnwood Discovery, we have a team of experienced peptide chemists who are skilled in succeeding with such challenges. Below is a case study that highlights Charnwood Discovery’s expertise and ability to meet the needs of highly demanding complex cyclic peptide projects for fast synthetic turnaround.

Synthesis of Cyclic Peptides_automated SPPS

Challenges

Synthesizing around 200 cyclic peptides swiftly posed a challenge, especially given the incorporation of unnatural amino acids. The targets often requiring the synthesis of complex, customized amino acids prior to solid-phase peptide synthesis (SPPS).

What We Did...

  • Employing various resin classes strategically throughout the project, tailored to specific peptide requirements and synthesis modifications.
  • Utilized automated SPPS predominantly, reserving manual SPPS for more intricate peptides.
  • Designing and synthesizing cyclic peptides with ring sizes ranging from 4 to 9 mer, meticulously considering factors such as ring strain to ensure successful cyclization.
  • Implementing diverse cyclization methods based on peptide sequence, both on and off-resin.
  • Executing on-resin modifications, including click reactions and alkylations.
  • Conducting synthesis of peptoid amino acids both on and off-resin.
Synthesis of Cyclic Peptides_Cyclic Peptide structure
  • Undertaking synthesis and post-synthetic modifications of highly strained ring systems.
  • Adapting conditions as necessary to overcome challenges such as racemization and diketopiperazine formation.
  • Collaborating closely between our in-house purification team and synthetic chemists, resulting in the swift processing of crude peptides (<5% purity) to yield final products of ≥95% purity by UPLC-MS.
  • Leveraging the proximity of all teams to enable expedited processing, with resin loading to isolated purified peptide averaging a week.

Summary

With Bioscience, Chemistry and ADME/DMPK teams all under one roof we were able to successfully purify and deliver compound data within 24 hours. Due to the nature of chemistry it was sometimes difficult to produce more than 0.5 mg of the compounds however being on one site enabled our teams to share a stock solution.  
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