Author(s): Andre Gohier
Mentor(s): Andrew Roberts
Institution U of U
Peptides have emerged as highly specific treatment options with a broad range of therapeutic uses, including anti-bacterial, anti-cancer, and anti-viral applications. Since the mid-1980s, antibacterial drug discovery has declined, and existing drugs face increasing resistance from bacteria. Developing novel antibacterial treatments is crucial, and antimicrobial peptides (AMPs) offer promising solutions to combat multiple drug-resistant (MDR) bacteria. Jelliane peptides, a subclass of AMPs found in royal jelly, have shown potential against MDR bacteria, although their efficacy diminishes rapidly due to degradation in their naturally occurring linear peptide form. Cyclizing peptides increases stability, enhancing the effectiveness of jelliane peptides at low concentrations. Urazoles and their oxidized forms, triazolinediones, are site-selective reagents for biomolecule conjugation. Tyrosine-urazole cross-linking is achieved through a thermal induction strategy, while Histidine labeling uses rose bengal as a photosensitizer to produce singlet oxygen, which reacts with Histidine to generate a peroxide intermediate trapped by methyl-urazole reagents. Previous work by the Roberts laboratory provides a foundation for improving the urazole strategy. To avoid undesired side products, the semicarbazide intermediate was first cleaved from the resin, allowing for selective in situ urazole formation. These urazole peptides were then cyclized with Tyrosine residues to form a Tyrosine-urazole (Tyr-urz) cross-linked macrocycle. This C-N bond-forming reaction used N-chlorosuccinimide (NCS) as a chemical oxidant to produce an electrophilic triazolinedione intermediate, which was attacked by the phenol side chain of Tyrosine. The promising results demonstrated in this work provide a starting point for developing on-resin cyclization reactions. During my time in the Roberts lab, I developed methods for orthogonal urazole protection using acid-labile and allyl protectant groups. The acid-labile group allows for simultaneous cleavage of both the protectant group and the resin, reducing overall synthesis time. The allyl protectant group provides flexibility, enabling selective cleavage of the peptide or resin, which is beneficial for on-resin cyclization to allow for acid-free cleavage of the protectant group.This facilitates the synthesis and easy modification of jelliane peptides and subsequent cyclization. This work has the potential to offer solutions for treating bacterial infections resistant to conventional methods or where MDR strains are unresponsive to known treatments. Peptides, such as jelliane peptides, represent a special class of therapeutics that could provide treatments for otherwise untreatable bacteria. Future work will focus on expanding the variety of substituents that can be introduced onto the urazole and exploring its potential as a linker between different sites in peptide-based therapies.