Fungal metacaspase (MCA)

Fungal metacaspases are ancestral cysteine proteases belonging to the peptidase C14 family, which are structurally related to mammalian caspases but possess distinct substrate specificities (Uren et al., 2000). Unlike mammalian caspases that cleave after aspartic acid residues, metacaspases specifically target arginine or lysine residues at the P1 position (Madeira et al., 2019). These enzymes are found in plants, fungi, and protozoa but are notably absent in the human genome, making them highly attractive targets for selective antifungal drug development (Minina et al., 2020). In fungi, metacaspases serve as central regulators of programmed cell death (PCD) and are involved in managing cellular stress, protein aggregation, and aging (Shrestha et al., 2015). During fungal infections, these proteases help the pathogen adapt to the host environment and survive oxidative stress induced by the immune system. While no drugs targeting metacaspases are currently in clinical use, research into small-molecule inhibitors like Z-VRPR-fmk has demonstrated potential in sensitizing fungi to existing treatments and inducing proteotoxic stress (Madeira et al., 2019). Targeting these enzymes offers a strategy to combat multi-drug resistant fungal pathogens by exploiting a pathway that is fundamentally different from human apoptotic machinery.

Other names

MetacaspaseMCA1YCA1Type I metacaspaseType II metacaspaseArginine/Lysine-specific cysteine protease

Inhibition of the arginine/lysine-specific cysteine protease activity, which disrupts the fungal programmed cell death pathway and impairs the cell's ability to respond to environmental and proteotoxic stress (Madeira et al., 2019; Shrestha et al., 2015).