Driven by an increasing demand for peptide-based drugs, method development for peptide synthesis and modification has grown substantially over the past decade. Peptide therapeutics can exhibit significant protein-target binding affinities at low concentrations due to high target specificity. Additionally, peptides offer an advantage relative to small molecules in part due to their low toxicity upon metabolism. However, this value is often overshadowed by their susceptibility to premature degradation and thus, the inability to reach an established target <i>in vivo</i>. The modification of bioactive linear peptides by means of cyclization has proven to be a useful strategy to minimize peptide degradation and maintain target specificity. We have developed a method to macrocyclize the N-terminus of peptides with internal and C-terminal tyrosine (Tyr) residues. The method is inspired by the chemoselective reaction of N4-substituted 1,2,4-triazole-3,5-diones with Tyr residues reported by Barbas and coworkers in 2010. Our method incorporates an electrophilic 1,2,4-triazoline-3,5-dione at the N-terminus of a given peptide sequence. Buffered, aqueous oxidation conditions permit internal Tyr residues to react with the in situ generated electrophilic 1,2,4-triazoline-3,5-dione moiety to produce macrocyclic peptides.

Chemoselective peptide macrocyclization at tyrosine residues with 1,2,4-triazoline-3,5-diones

Macromolecular Chemistry: The Second Century

[Author Benefits](https://scimeetings.acs.org/?utm_source=pubs_content_marketing&utm_medium=website&utm_campaign=0320_MCF_NPI_Launch_Spring_Homepage&ref=pubs_content_marketing)

[How to use SciMeetings](https://storage.googleapis.com/dl.morressier.com/acs/SciMeetings-ACSSpring2020-HowToGuide_M3020-Final.pdf)

[Frequently Asked Questions](https://storage.googleapis.com/dl.morressier.com/acs/SciMtng_ACSNMSp2020_FAQ_M3120_Final.pdf)

ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.