Speaker: Joe Cannon, Merck
Topic: Simplifying Cyclic Peptide Hydrolysis Interpretation in Metabolite Identification
Date: Monday, September 21st, 2020
Time: 1:00 pm Presentation
Location: Webinar – see emails on Sept. 10 and 18 for invite link. Join the mailing list
Abstract: Peptides, as therapeutics, can be used to disrupt crucial protein-protein interactions in disease states. As a modality, they offer an exciting compromise between large molecule-like specificity and small molecule-like absorption and distribution, all without the need for orthosteric binding. Despite these favorable properties, peptides suffer from short in vivo half-life due to protease mediated hydrolysis. To combat this, peptides are often conjugated and internally crosslinked to enhance rigidity or cyclized to decrease susceptibility to amino and carboxypeptidases. For linear peptides, identifying the site of hydrolysis is simple and similar to peptide identification in proteomics experiments. For cyclized peptides, it is very challenging due to the fact that hydrolysis simply linearizes the molecule, and the mass of a peptide from hydrolysis at one position is isobaric with every other position. 2-pyridine carboxaldehyde (2PCA) is used here to selectively conjugate the N-terminal amino acid and provide an amino acid specific low mass reporter fragment ion doublet that points to the site of hydrolysis. The chemistry is demonstrated here on a HeLa tryptic digest and proof-of-concept studies are shown on cyclic peptides.