Identification of a novel yeast-derived peptide as positive allosteric modulator of AT1R

Natural products represent a vital source for drug discovery targeting G protein-coupled receptors (GPCRs). Among them, bioactive peptides have emerged as promising therapeutic candidates owing to their high selectivity and low toxicity. In this study, we investigated the modulatory effects of peptides derived from Saccharomyces cerevisiae on the angiotensin II (AngII) type 1 receptor (AT1R), a class A GPCR that plays a central role in cardiovascular homeostasis. We identified a heptapeptide TLPPPPL (TLP) that enhances AngII binding to AT1R without altering maximal binding capacity, as determined by an HTRF-based ligand-binding assay. Functional analyses using BRET-based biosensors revealed that TLP acts as a positive allosteric modulator, potentiating both G protein activation and β -arrestin recruitment. Furthermore, TLP augments signaling induced by biased AT1R agonists and rescues the impaired function of disease-associated AT1R mutants, indicating a broad positive modulatory effect on agonist-driven receptor activation. Together, these findings identify a yeast-derived positive allosteric modulator of AT1R and underscore the potential of natural peptides as promising leads for the development of GPCR-targeted therapeutics.