Practical ring-opening strategy for the sequence determination of cyclic peptides from one-bead-one-compound...

Area of Science:

• Chemical Biology
• Organic Chemistry
• Analytical Chemistry

Background:

• Cyclic peptides are valuable in drug discovery but challenging to sequence in one-bead-one-compound libraries.
• Traditional sequencing methods like Edman degradation and tandem mass spectrometry are often ineffective for cyclic peptides due to their structure.

Purpose of the Study:

• To develop a robust method for sequencing cyclic peptides within one-bead-one-compound libraries.
• To overcome the limitations of existing sequencing techniques for cyclic peptide identification.

Main Methods:

• A novel approach was designed using a methionine residue incorporated within the cyclic peptide macrocycle and as a linker.
• Cyanogen bromide treatment was employed for simultaneous ring-opening and release from the resin.
• Peptides were analyzed using MALDI-TOF MS/MS and sequenced manually and with de novo software.

Main Results:

• The developed method successfully enabled the sequencing of cyclic peptides released from single beads.
• The strategy is compatible with standard amino acids, simplifying its application.
• This approach circumvents the need for complex encoding methods previously required.

Conclusions:

• The novel methionine-based strategy effectively addresses the challenge of sequencing cyclic peptides in combinatorial libraries.
• This technique enhances the utility of one-bead-one-compound libraries for cyclic peptide discovery.
• The method offers a more efficient alternative to existing sequencing protocols, reducing experimental complexity.