Keyes, E. Dalles; Alvey, Brighton; Smith, T. Andrew; Roberts, Andrew G. (University of Utah)
Faculty Advisor: Roberts, Andrew G. (University of Utah, Chemistry)
Medicinal chemistry has long relied on the development of small molecule therapeutics to treat human disease. Small molecules affect change at the cellular level through specific interactions with biological targets (e.g. proteins), thereby eliciting a desired physiological response. Conversely, small molecules can also interact non-specifically, which can complicate their targeted application. In many cases, the use of peptide-based medicines can address this limitation. Like small molecules, peptide-therapeutics are designed to modulate specific biological processes. They often exhibit desirable activity at low concentrations as a result of high selectivity. Being comprised of natural amino acid building blocks, peptides offer an inherent advantage. Their natural breakdown leads to minimally toxic degradation products. However, premature and rapid degradation can result in failure to reach an established target in vivo. The cyclization of peptides has shown to be a promising strategy to address this problem. Inspired by Nature's wide collection of non-ribosomal peptides, specifically those comprising electron-rich aromatic moieties, we have developed a new chemical strategy for the synthesis of cyclic peptides. Our cyclization method leverages the inherent reactivity of the tyrosine (Tyr) phenol nucleus with electrophilic 1,2,4-triazoline-3,5-dione (TAD) moieties. Using this reaction, we can construct macrocyclic peptidomimetic scaffolds. Upon synthesizing an N4-substituted 1,2,4-triazolidine-3,5-dione (aka urazole) at the N-terminus of a solid-supported peptide, the urazole moiety is chemoselectively oxidized under mild conditions to generate a TAD derivative in situ. The TAD moiety reacts with the sidechain phenol nucleus of internally or terminally located Tyr residues and results in the formation of a macrocyclic peptide. We envision that this method will significantly augment current strategies for constructing macrocyclic peptides by enabling the facile synthesis of complex peptidomimetic scaffolds. Furthermore, this approach is anticipated to expand the repertoire of tools used for developing medicinally relevant peptides and, thus, may be suitable for preparing unique peptide-based therapeutics.