Sethera Therapeutics Announces Enzymatic Platform for Advanced Peptide Drug Development

Sethera Therapeutics has published peer-reviewed results in the Proceedings of the National Academy of Sciences (PNAS) 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 and expanding accessible chemical space for peptide therapeutic design.

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. Karsten Eastman, PhD, CEO and co-founder of Sethera, explained that while most people picture enzymes as molecular scissors, their radical-based enzymatic technology acts like a precise molecular stapler, architecting new peptide structures and locking them into stable, drug-like shapes.

Vahe Bandarian, PhD, Professor of Chemistry and Associate Provost for Mission-Aligned Planning at the University of Utah and co-founder of Sethera, emphasized the importance of basic research, noting that Utah's translational ecosystem and sustained NIH support in fundamental chemistry and enzymology made this discovery possible. The platform exemplifies how federal, state, and university partners can turn bench science into significant 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. Eastman added that what's distinctive is the breadth with precision, as their technology handles many sequences while directing exactly where the bond forms.

Unlike disulfide bonds found in many natural peptides such as 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. Eastman noted that since GLP-1s are peptides, insulins are peptides, and many natural hormones are peptides, the platform directly connects to designing the next generation of peptide therapeutics.