Sethera Therapeutics Announces Enzymatic Platform for Advanced Peptide Drug Development
TL;DR
Sethera Therapeutics' enzymatic stapling platform offers a competitive edge by enabling more stable and orally deliverable peptide therapeutics with reduced development complexity.
Sethera's radical SAM maturase enzyme precisely forms thioether staples on diverse peptide substrates including non-natural building blocks through controlled enzymatic crosslinking.
This technology advances peptide medicine development, potentially improving treatments for diabetes and other conditions through more effective and accessible therapeutic options.
Sethera's enzyme acts as a molecular stapler, creating durable peptide structures that defy traditional enzyme mechanisms with remarkable precision and versatility.
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Sethera Therapeutics has published groundbreaking research in the Proceedings of the National Academy of Sciences detailing an enzymatic crosslinking platform that creates durable thioether staples, enabling the development of next-generation peptide therapeutics. The platform, described in the paper "Diverse Thioether Macrocyclized Peptides Through a Radical SAM Maturase," represents a significant advancement in peptide drug design by locking peptides into stable, drug-like cyclic architectures.
The technology demonstrates exceptional versatility, working 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, "Most people picture enzymes as molecular scissors, 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."
The platform's significance lies in its ability to defy traditional enzymatic models, showing broad substrate scope with precise bond placement. This controlled "promiscuity" allows the technology to reliably staple diverse peptide sequences while accepting non-natural building blocks including D-amino acids, β-amino acids, and N-methyl residues. This capability expands accessible chemical space and enables the design of peptides composed entirely of non-natural components.
Unlike disulfide bonds found in many natural peptides such as insulin, Sethera's thioether staples are chemically robust and protease-resistant, significantly improving stability and pharmacological behavior. This enhanced stability potentially supports oral delivery of peptide drugs, addressing a major limitation in current peptide therapeutics. The team demonstrated the platform's capability to reconstruct sophisticated macrocyclic scaffolds often used to achieve passive cell permeability, accomplishing in a single enzymatic step what typically requires complex multi-step synthetic chemistry.
The development of this platform was made possible through collaboration with researchers in the Department of Chemistry at the University of Utah. Vahe Bandarian, PhD, Professor of Chemistry and Associate Provost for Mission-Aligned Planning at the University of Utah and co-founder of Sethera, emphasized that "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."
This technological advancement has profound implications for the pharmaceutical industry, particularly in the development of peptide-based therapeutics. As Eastman noted, "GLP-1s are peptides; insulins are peptides; many natural hormones are peptides. The platform we're building directly connects to designing the next generation of peptide therapeutics." The platform's ability to create more effective, stable, and deliverable peptide medicines positions Sethera to lead innovation in peptide therapeutics, potentially transforming treatment options for various diseases.
Curated from Reportable
