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Triazolinedione (TAD)-based Tryptophan-Selective Cyclization

Semester: Summer 2023


Presentation description

Synthetic biology has made significant strides, reaching levels comparable to total chemical synthesis, with the preparation of natural and engineered biological macromolecules, proteins, and genomes from simple chemical building blocks. In the field of drug therapeutics, research has focused on small molecules and proteins, not macrocycles and peptides. In therapeutic design, small molecules face limitations due to their size and scaffold area, whereas peptides offer a larger size and scaffold. However, peptides present challenges in reducing the degradation of natural peptide sequences. Cyclic peptides demonstrate greater stability than linear peptides, owing to their unique biological motif, which allows for flexible design space. To elevate the study of macrocyclic peptides to a higher level, a novel approach was developed to selectively cyclize peptides at an internal or terminal Tyrosine, creating natural product peptides without complex or time-consuming reactions. This cyclization method has been applied to peptides containing Tryptophan residues, opening the door to further investigations of macrocyclic peptides. Triazolinediones (TADs) are electrophilic dienophiles with remarkable chemoselective reactivity that when substituted can be used for Tyr- and Trp-selective bioconjugation reactions that satisfy 'click reaction' chemical requirements. To create a TAD-peptide, a urazole moiety was attached to the N-terminal amino acid residue of a peptide and oxidized using N-chlorosuccinimide. When exposed to basic conditions, this TAD-peptide produced a Trp-linked cyclic peptide that was increasingly stable with a constricted conformation that rendered the peptide biologically active. By advancing our understanding of macrocyclic peptides, this research promises to contribute significantly to the field of drug therapeutics.

Presenter Name: Zoe Brown

Presentation Type: Poster
Presentation Format: In Person
Presentation #89
College: Science
School / Department: Chemistry
Research Mentor: Andrew Roberts
Date | Time: Thursday, Aug 3rd | 9:00 AM