Cyclative Release Strategy to Obtain Pure Cyclic Peptides Directly from the Solid Phase.

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Peptide Chemistry

Background:

• Current methods for synthesizing cyclic peptides, essential for drug development screening, are hampered by the requirement for individual purification.
• This purification step is time-consuming and limits the scale of cyclic peptide library generation.

Purpose of the Study:

• To develop a novel strategy for the direct synthesis of pure cyclic peptides from solid-phase support, bypassing the need for purification.
• To enable high-throughput synthesis and screening of cyclic peptide libraries for drug discovery.

Main Methods:

• Peptides with an N-terminal thiol group were synthesized on a solid phase using a C-terminal disulfide linker.
• Sidechain-protecting groups were removed while the peptides remained on the solid phase.
• Cyclization was achieved by adding a base to deprotonate the N-terminal thiol, triggering an intramolecular disulfide-exchange reaction for release.

Main Results:

• The developed method successfully yields disulfide-cyclized peptides directly in pure form, without requiring chromatographic purification.
• The strategy is amenable to facile synthesis in 96-well plates, facilitating the production of hundreds of cyclic peptides.
• The resulting cyclic peptides are in a format similar to important peptide drugs like oxytocin and vasopressin.

Conclusions:

• This novel solid-phase synthesis strategy significantly streamlines the production of cyclic peptides.
• The method overcomes purification bottlenecks, enabling efficient generation and screening of diverse cyclic peptide libraries.
• The approach holds promise for accelerating drug discovery efforts by providing rapid access to valuable cyclic peptide therapeutics.