Sethera Therapeutics has published peer-reviewed results in the Proceedings of the National Academy of Sciences (PNAS) describing an enzymatic crosslinking platform that creates durable thioether staples, locking peptides into drug-like cyclic architectures. This technology represents a significant advancement in peptide therapeutic development, offering exceptional versatility and expanding accessible chemical space for drug design.
The platform, detailed in the paper titled Diverse Thioether Macrocyclized Peptides Through a Radical SAM Maturase, works across a broad range of substrates, including sequences built entirely from non-natural building blocks. According to Karsten Eastman, PhD, CEO and co-founder of Sethera, the radical-based enzymatic technology acts 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 versatility distinguishes the technology from conventional methods that often require complex multi-step synthetic chemistry.
The thioether staples created by this platform are chemically robust and protease-resistant, offering significant advantages over disulfide bonds found in many natural peptides such as insulin. This improved stability enhances pharmacological behavior and potentially supports oral delivery of peptide therapeutics, addressing a major limitation in current peptide drug development. 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 synthetic chemistry.
The development of this platform connects directly to designing the next generation of peptide therapeutics, including GLP-1 analogs, insulins, and natural hormones. The technology's ability to handle many sequences while directing exactly where bonds form provides unprecedented control over peptide architecture, potentially leading to more effective and stable peptide medicines. This advancement could significantly impact the pharmaceutical industry by enabling the development of peptide drugs with improved stability, delivery options, and therapeutic efficacy.
