Sethera Therapeutics Unveils Breakthrough Enzymatic Platform for Next-Generation Peptide Drugs

SALT LAKE CITY, Utah August 21, 2025 — Sethera Therapeutics today announced publication in the Proceedings of the National Academy of Sciences (PNAS) of peer-reviewed results describing an enzymatic crosslinking platform that forges durable thioether “staples,” locking peptides into drug-like cyclic architectures. The platform works across a broad range of substrates, including sequences built entirely from non-natural building blocks, delivering exceptional versatility, expanding accessible chemical space, and enabling the design of next-generation peptide therapeutics.

The paper, titled “Diverse Thioether Macrocyclized Peptides Through a Radical SAM Maturase,” was co-authored by Sethera Therapeutics and collaborators in the Department of Chemistry at the University of Utah.

“Most people picture enzymes as molecular scissors,” said Karsten Eastman, PhD, CEO and co-founder of Sethera. “But enzymes also build. Our radical-based enzymatic technology acts like a precise ‘molecular stapler,’ architecting new peptide structures and locking them into stable, drug-like shapes.”

“Basic research matters,” said Vahe Bandarian, PhD, Professor of Chemistry and Associate Provost for Mission-Aligned Planning at the University of Utah and co-founder of Sethera. “Utah’s translational ecosystem and sustained NIH support in fundamental chemistry and enzymology made this discovery possible. Sethera exemplifies how federal, state, and university partners turn bench science into unsurpassed societal impact."

Defying the classic lock-and-key or induced-fit view of enzymes, Sethera’s platform shows broad substrate scope with pinpoint bond placement, what scientists call controlled “promiscuity.” The process reliably staples diverse peptide sequences and accepts non-natural building blocks, including D-amino acids, β-amino acids, and N-methyl residues, even enabling peptides composed entirely of non-natural components.

“What’s distinctive here is breadth with precision, our technology handles many sequences while directing exactly where the bond forms,” Eastman added.

Unlike disulfide bonds found in many natural peptides (e.g., insulin), Sethera’s thioether staples are chemically robust and protease-resistant, improving stability and pharmacological behavior and potentially supporting oral delivery. The team demonstrated reconstruction of sophisticated macrocyclic scaffolds often used to achieve passive cell permeability, accomplishing in a single enzymatic step what typically demands complex multi-step synthetic chemistry.

“GLP-1s are peptides; insulins are peptides; many natural hormones are peptides,” Eastman said. “The platform we’re building directly connects to designing the next generation of peptide therapeutics.”