University of Utah Researchers Discover PapB Enzyme for Enhanced Peptide Drug Development
核心洞察
Researchers at the University of Utah have identified PapB, a naturally-occurring enzyme that can transform linear peptides into stable circular molecules, potentially improving GLP-1 (搜索) drugs like semaglutide for diabetes (搜索) and obesity (搜索) treatment.
The enzyme creates thioether-linked macrocycles without requiring leader sequences, offering a simpler alternative to traditional chemical methods for peptide cyclization and enabling better stability and longer half-life.
PapB's flexibility allows it to work with nonstandard amino acids found in modern incretin drugs, potentially creating next-generation peptide therapeutics that can target previously "undruggable" targets.
Researchers at the University of Utah, in collaboration with Utah-based Sethera Therapeutics (搜索), have discovered an enzymatic approach that could revolutionize peptide drug development by creating more stable and effective therapeutic compounds. Their findings, published in Proceedings of the National Academy of Sciences (PNAS), demonstrate how PapB, a naturally-occurring enzyme from Paenibacillus polymyxa bacteria, can transform linear peptides into robust circular molecules suitable for drug development.
Revolutionary Enzymatic Approach
PapB is a radical S-adenosyl-L-methionine (SAM) enzyme that constructs thioether-linked macrocycles in peptides. Unlike traditional chemical methods for peptide cyclization, which can be expensive and challenging late in drug development, PapB offers a much simpler alternative by naturally forming precise chemical bonds that close peptide chains into rings without requiring the "leader" sequences most enzymes need to recognize their targets.
"We never expected [PapB] to do what it did," said Vahe Bandarian, Sethera CSO and professor of chemistry at the University of Utah. "We're taught that enzymes are very specific – they do a certain reaction and nothing else. PapB is pretty special."
The enzyme joins an internal cysteine thiol to a peptide's C-terminal carboxylate, producing robust macrocycles by introducing six thioether linkages between internal Cys residues and carbon atoms α to the side-chain carboxylate of Asp/Glu residues C-terminal to the Cys residues.
Addressing Peptide Stability Challenges
Many current peptide drugs rely on disulfide bonds for stabilization, but these bonds are inherently unstable in reductive physiological environments, limiting therapeutic applications. PapB addresses this limitation by creating more stable cyclic structures.
"Linear peptides are great because they can act on a specific target and then be quickly recycled. Our bodies are incredible at recycling short chains of amino acids," explained Karsten Eastman, CEO and co-founder of Sethera and lead author of the study. "One way to get around this is to give a peptide more proteolytic stability by cyclizing it so your body can't chop it up as easily."
Laboratory tests confirmed that PapB successfully formed rings even when peptides contained nonstandard building blocks found in many modern incretin drugs. "We were surprised by how flexible the enzyme turned out to be," said Jake Pedigo, lead author and graduate student in the Bandarian lab. "It didn't need the usual leader sequence and it still worked even when we swapped in unusual amino acids."
Implications for GLP-1 Drug Enhancement
The discovery has particular relevance for improving GLP-1 (搜索) medications such as semaglutide, the active ingredient in Ozempic and Wegovy used to treat diabetes (搜索) and obesity (搜索). The team demonstrated that PapB could connect the ends of GLP-1-like peptides through sulfur-carbon thioether bonds, potentially creating stronger, longer-lasting versions of these therapeutics.
"You have these peptides that could have a great biological response, but if that biological response only lasts minutes, then all of a sudden you don't have a good therapeutic," Eastman noted. "By using this enzymatic method to tie off the ends, we are essentially hiding the peptide from some of the most common proteases (搜索) in the body – which are what breaks down peptides. This would enable the longer half-life."
Targeting "Undruggable" Proteins
One of the most significant implications of this research is the potential to design peptide therapeutics that can reach previously "undruggable targets." The platform's ability to create poly-macrocyclic peptides enables targeting multiple proteins simultaneously.
"Since we are a poly-macrocyclic peptide platform, we can go after multiple targets at the same time," Eastman said. "There are many cancer (搜索) indications where it's not just one over expressed target that is a problem – there are multiple. This is why bispecific and trispecific antibody therapies have been rising in popularity and clinical efficacy. We are hoping to accomplish the same thing, but with a peptide."
The approach could potentially achieve the same multi-target effects as large antibodies (100-150 kilodaltons) using much smaller peptide molecules, offering advantages in terms of manufacturing, delivery, and potentially reduced immunogenicity.
Commercial Development and Future Applications
The researchers are actively seeking partnerships to utilize their platform as a screening tool in drug development. "Right now, we're actively searching for a partner and have had a lot of talks in terms of using the platform as a screening tool to start looking for the best hits," Eastman continued.
The team believes their enzymatic method could become an indispensable tool in drug development, particularly for creating peptide therapeutics with improved targeting, cell penetration, and oral dosing capabilities. "Big pharma's GLP-1 (搜索) backbones are already excellent," Eastman said. "What we're adding is a clean, late-stage enzymatic step that can make those molecules work even harder. By installing a small, well-defined ring, we can tune how long the drug lasts, how stable it is and even how it signals – all while staying compatible with the complex structures already in use."