Scientists at Ca' Foscari University of Venice, in collaboration with researchers from Japan, China, Switzerland, and Italy, have developed an innovative method to produce and rapidly analyze a vast array of macrocyclic peptides, molecules increasingly used in modern medicine. The research, published in Nature Communications, harnesses the familiar brewer's yeast, turning billions of these tiny organisms into miniature fluorescent factories, each capable of creating a unique peptide with potential therapeutic applications.
Macrocyclic peptides are promising drugs because they combine precision targeting, stability, and safety, offering fewer side effects than traditional drugs. However, conventional methods for discovering and testing these peptides are often complex, difficult to control, slow, and environmentally unfriendly.
To overcome these limitations, the researchers engineered common brewer's yeast cells to individually produce different macrocyclic peptides. Each yeast cell acts like a tiny factory that lights up when prod-ucing the compound, allowing scientists to swiftly identify promising peptides. Using advanced fluorescence-based techniques, the team screened billions of these micro-factories in just a few hours, a process that is significantly faster and more ecofriendly than existing methods.
Sara Linciano, lead author and postdoctoral researcher at Ca' Foscari's Department of Molecular Sciences and Nanosystems, explains: "We manipulated yeast cells so that each one functions as a 'micro-factory' that becomes fluorescent when producing a specific compound. This allowed us to analyze 100 million different peptides rapidly and effectively."
Ylenia Mazzocato, co-leader of the study, highlights the sustainability of their approach: "By exploiting the natural machinery of yeast, we produce peptide molecules that are biocompatible and biodegradable, making them safe for health and the environment, a truly 'green pharma' approach."
The team also clarified how these peptides precisely bind to their targets. Zhanna Romanyuk, who contributed to the structural analysis, says: "Using X-ray crystallography, we demonstrated the excellent binding properties of these peptides, confirming their precision and potency."
This new method offers significant advancements for drug discovery, especially for challenging targets that conventional drugs cannot easily address. Alessandro Angelini, associate professor and study coordinator, emphasizes: "We are pushing the boundaries of this technology to create macrocyclic peptides that can deliver advanced therapies directly to specific cells, potentially revolutionising treatments. This could greatly benefit patient health and have substantial scientific and economic impacts."
This work was part of the National Recovery and Resilience Plan (PNRR), supported by the European Union's Next Generation EU initiative, involving multidisciplinary teams from Ca' Foscari University of Venice, Kyoto Institute of Technology (KIT), Chinese Academy of Sciences, University of Padova, and École Polytechnique Fédérale de Lausanne (EPFL), including experts in chemistry, biophysics, biochemistry, and computational sciences.
Part of this technology has already been patented by Ca' Foscari and was recently acquired by the startup Arzanya S.r.l. "Seeing our technology gain international recognition makes me proud," Angelini concludes. "I I hope Arzanya S.r.l. can provide our talented young researchers with the opportunity to pursue their passions here in Italy, without necessarily needing to move abroad."