Developing novel antifungals: lessons from G protein-coupled receptors

Integral membrane proteins found in the plasma membrane of fungi have great potential for the development of novel antifungal agents.In-depth studies on fungal signaling pathways define proteins that when deleted result in decreased virulence or viability, highlighting their potential as drug targets.New tools and methodologies have been developed to determine the structure of the yeast pheromone-sensing G protein-coupled receptor (GPCR) Ste2, highlighting the tractability of fungal GPCRs for structure determination.Single-particle electron cryo-microscopy was used to determine five structures of Ste2 that show the molecular details of ligand-induced receptor activation and highlight possible receptor regions that are amenable for drug development. Up to 1.5 million people die yearly from fungal disease, but the repertoire of antifungal drug classes is minimal and the incidence of drug resistance is rising rapidly. This dilemma was recently declared by the World Health Organization as a global health emergency, but the discovery of new antifungal drug classes remains excruciatingly slow. This process could be accelerated by focusing on novel targets, such as G protein-coupled receptor (GPCR)-like proteins, that have a high likelihood of being druggable and have well-defined biology and roles in disease. We discuss recent successes in understanding the biology of virulence and in structure determination of yeast GPCRs, and highlight new approaches that might pay significant dividends in the urgent search for novel antifungal drugs.