Nutrient sensing G protein-coupled receptors: interesting targets for antifungals?

Abstract

G protein-coupled receptors (GPCRs) are important targets for various drugs that are on the market. An important area in which we urgently need novel drug targets is the field of antifungals. Recently a new class of nutrient sensing G protein-coupled receptors have been identified in fungi. The founding member of this novel class of GPCRs is Gpr1, the sucrose/glucose sensing receptor of Saccharomyces cerevisiae. This receptor activates the cAMP-PKA pathway that is important for the yeast-to-pseudohypha transition and for stress tolerance. The capacity to change morphology is an important virulence factor for pathogenic fungi and it has been shown in these fungi that morphogenesis also depends on the cAMP-PKA pathway. Therefore, functional Gpr1 homologous receptors in these fungi may be interesting targets for antifungals. Despite the fact that these receptors are not essential for growth, modification of their activity may affect fitness of the fungus allowing the human or plant defense systems to win the battle. In addition, synthetic avirulent interactions, such as the one observed between the C. albicans Gpr1 and the trehalose-6-phosphate phosphatase enzyme, may be a tool to come up with a good combination therapy approach. It will be necessary to identify antagonists or inverse agonists for these receptors, which will require good screening systems and large compound libraries.

GPCR, Saccharomyces cerevisiae, filamentous fungi, nutrient sensing, antifungal drug