Fungal pathogen cell wall proteins and structural protein–polysaccharide interfaces

The fungal cell wall is a complex and dynamic extracellular matrix essential for the survival, structural integrity, and virulence of fungal pathogens. It is primarily composed of a core scaffold of polysaccharides, including chitin and beta-glucans, which are covalently linked to an outer layer of cell wall proteins (CWPs). These proteins, many of which are glycosylphosphatidylinositol (GPI)-anchored, are critical for maintaining the mechanical strength of the wall, mediating adhesion to host tissues, and facilitating the formation of biofilms. The structural protein–polysaccharide interfaces represent the specific covalent bonds and molecular interactions that integrate these proteins into the polysaccharide matrix. Disruption of these interfaces, particularly through the inhibition of enzymes like Gwt1 (an inositol acyltransferase involved in GPI anchor biosynthesis), has emerged as a potent antifungal strategy. Drugs such as fosmanogepix (and its active moiety manogepix) target this process, leading to the loss of cell wall proteins, compromised wall integrity, and reduced pathogenicity, making them promising candidates for treating invasive fungal infections.

Other names

Fungal cell wall proteinsCWPsProtein-polysaccharide interfacesGPI-anchored proteinsPir proteinsMannoproteins

Inhibition of Gwt1 (inositol acyltransferase), which prevents the maturation and localization of GPI-anchored cell wall proteins.