Nature-derived peptide libraries for GPCR ligand discovery

Bioactive peptides occur in all domains of life. Cyclotides are plant peptides comprising a circular backbone and three interlocked disulfide bonds that confer them with exceptional stability. This unique structure makes them interesting pharmaceutical tools for the development of orally bioavailable peptide-based drugs. Cyclotides exhibit several intrinsic biological activities, but the detailed molecular mechanisms of their effects have been studied in very few cases. For example, we have recently demonstrated that the cyclotide kalata B7 interacts with the human oxytocin and vasopressin V1a-receptors, belonging to the family of G protein-coupled receptors (GPCRs). These findings offer the unique opportunity to test whether cyclotides can target other GPCRs. Our scientific project aims to discover cyclotides and to use these nature-derived molecules as templates to design novel ligands for GPCRs; these transmembrane proteins constitute the most important class of therapeutic drug targets. To reach our objectives, we combine state-of-the-art pharmacological, chemical and bioanalytical approaches. If successful, these findings offer starting points for drug development of circular peptides to clinical relevant GPCRs.

Our project, entitled "Nature-derived peptides as libraries for GPCR ligand discovery," focuses on the exploration of circular peptides from plants to develop novel ligands for G protein-coupled receptors (GPCRs). This category of receptors is pivotal in therapeutic drug targeting. Our collaborative efforts blend advanced pharmacological, chemical, and bioanalytical methods. Significant progress includes establishing peptide-based GPCR ligands from diverse plant extracts and designing peptides that modulate the activity of key receptors like kappa-opioid and cannabinoid receptors. Notably, our research has led to the discovery of novel peptide ligands with potential therapeutic applications as analgesics or for autoimmune disorders, showcasing the immense potential of nature-derived molecules in medical science.