University of Utah Research Enables Enzymatic Modification of GLP-1 Peptides Without Leader Sequence Requirements

A University of Utah research team has demonstrated that a radical enzyme can modify therapeutic peptides into compact rings without the typical leader-sequence requirements, representing a significant advancement in peptide drug development. This innovation is now progressing toward clinical applications through Utah-based spinout company Sethera Therapeutics, with findings published in the prestigious ACS Bio & Med Chem Au Journal.

The research addresses critical limitations in GLP-1 receptor agonists, which have revolutionized diabetes and obesity treatment but face ongoing challenges with peptide stability and tissue targeting. The enzymatic approach developed by the Utah team offers a programmable modification strategy that can be applied late in drug development cycles without requiring extensive re-engineering of existing compounds.

Jacob Pedigo, first author from the Vahe Bandarian Lab in the Department of Chemistry, employed multiple analytical methods to confirm clean C-terminal thioether macrocyclization on GLP-1 pathway analogs. The team discovered that the rSAM maturase PapB enzyme can function leader-independently, creating the intended thioether ring even when the recognition element domain is deleted or when the leader sequence is replaced with unrelated sequences.

This combination of mechanistic specificity with substrate promiscuity represents a breakthrough in translational efficiency, as researchers can apply the same biocatalyst across multiple peptide sequences with minimal re-engineering requirements. Pedigo noted that the enzyme's tolerance for non-native leaders, swapped leaders, and non-canonical residues while still producing clean, single-ring products makes PapB a practical tool rather than merely an interesting mechanism.

The implications for patient outcomes are substantial, as a compact C-terminal ring can block protease degradation, stabilize receptor-binding conformations, and serve as a programmable handle for half-life extension or tissue targeting. These features are central to the development of next-generation incretin medicines that could offer improved efficacy and reduced side effects.

Vahe Bandarian, Professor of Chemistry and Chief Scientific Officer at Sethera Therapeutics, emphasized that PapB delivers specific chemistry while relaxing sequence rules that typically slow translation. This opens practical pathways to fine-tune approved peptide scaffolds late in development, potentially improving stability, signaling bias, and tissue targeting using a single, well-characterized enzyme.

The University of Utah holds patent interests in these findings, reflecting the institution's commitment to research commercialization. Sethera Therapeutics, co-founded by Bandarian and Karsten A. S. Eastman, is advancing the technology toward clinical applications. The research received support from the National Institutes of Health through grants R35 GM126956 and T32 GM122740, demonstrating how federal investment in scientific research fuels local company development and drives clinical innovation.

This enzymatic platform technology represents a significant advancement in peptide-based drug development, potentially accelerating the creation of more stable and targeted therapeutics for metabolic diseases. The ability to modify peptides without traditional sequence constraints could streamline drug development pipelines and enable more precise therapeutic targeting, ultimately benefiting patients through improved treatment options for diabetes, obesity, and related conditions.