Chasing immunomodulatory peptides from underexplored plants and fungi

Objective

Autoimmune diseases and related inflammatory disorders are worldwide on the rise, underscoring the urgent need to better understand how immune responses of the body can be modulated. While natural products have long provided leads for drug discovery, research has focused primarily on small molecules extracted with organic solvents. In contrast, peptides from aqueous extracts remain an underexplored natural resource, even though accumulating evidence suggests that such peptides can profoundly affect immune cell activity. This neglected space offers a unique opportunity for peptide discovery. Our project will systematically investigate chemical extracts of >240 organisms, with scarcity of studies associated with their peptide production, around two-thirds of which have never been studied for their peptide content, despite some having a long tradition of use in treating immune-related conditions. Using an integrated peptidomics approach that we currently establish with the Biodiversa+ network ‘Biodiversity2Drugs’, we will first predict peptide sequences in genome/transcriptome datasets with potential activity at immune cell G protein-coupled receptors, allowing us to prioritize candidates. These most promising plant and fungus species will then be selected for detailed study. They will be processed with optimized aqueous extraction protocols, followed by fractionation, isolation and de novo peptide sequencing to identify bioactive peptides. Where natural quantities are insufficient, synthetic versions will be prepared. Finally, these purified peptides will be tested for their ability to bind to and modulate specific receptor pharmacology, and to influence immune cell function using an array of second messenger, cell sorting and cytokine release assays. Our study seeks to broaden the chemical and biological space of immunomodulatory compounds, advancing fundamental knowledge on how nature may help to provide tools and drug leads for understanding immune cell signaling.