Biocompatible and Selective Generation of Bicyclic Peptides

Area of Science:

• Chemical synthesis
• Medicinal chemistry
• Biotechnology

Background:

• Bicyclic peptides offer advantages for drug discovery but face synthetic challenges.
• Existing methods are often not biocompatible or fully orthogonal.
• Developing efficient and versatile bicyclic peptide synthesis is crucial.

Purpose of the Study:

• To develop a straightforward, biocompatible, and automatable method for synthesizing complex bicyclic peptides.
• To demonstrate the utility of this method for creating tailored bicyclic peptides with desirable drug-like properties.
• To validate the approach using specific examples like a Zika virus protease inhibitor and antimicrobial peptides.

Main Methods:

• Utilized a selective reaction between 1,2-aminothiols and 2,6-dicyanopyridine.
• Employed standard solid-phase peptide synthesis for full automation.
• Performed bicyclization in aqueous solution at physiological pH without a catalyst.

Main Results:

• Achieved direct access to complex bicyclic peptides in high yield.
• Demonstrated rapid, biocompatible, and catalyst-free bicyclization in water.
• Showcased the ability to create tailored bicyclic peptides with improved plasma stability, conformational preorganization, and high target affinity.
• Successfully synthesized bicyclic inhibitors of Zika virus protease and modified antimicrobial peptides.

Conclusions:

• The developed method provides a highly efficient and versatile route to complex bicyclic peptides.
• This approach overcomes limitations of traditional bicyclic peptide synthesis, enabling broader applications in drug discovery.
• The synthesized bicyclic peptides exhibit promising properties for therapeutic development.