Sethera Therapeutics Announces Enzymatic Platform for Advanced Peptide Drug Development

Sethera Therapeutics 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 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. CEO Karsten Eastman described the technology as acting like a precise molecular stapler, architecting new peptide structures and locking them into stable, drug-like shapes. Unlike traditional enzymatic approaches, Sethera's platform demonstrates 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. This technological advancement represents a significant departure from conventional peptide synthesis methods that typically require complex multi-step synthetic chemistry.

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 while 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 extensive synthetic effort.

Professor Vahe Bandarian of the University of Utah emphasized the importance of basic research and translational ecosystems in making this discovery possible, noting that sustained NIH support in fundamental chemistry and enzymology contributed to the development. The platform's ability to handle many sequences while directing exactly where bonds form represents a distinctive combination of breadth and precision in peptide engineering.

This technological breakthrough has significant implications for the pharmaceutical industry, particularly in the development of peptide-based therapeutics. Given that GLP-1 drugs, insulins, and many natural hormones are peptides, Sethera's platform directly connects to designing the next generation of peptide medicines with improved stability, delivery options, and therapeutic potential. The ability to create entirely non-natural peptide structures opens new avenues for drug discovery and development that were previously inaccessible through conventional synthetic methods.