Fungal infections including athlete’s foot and ringworm are common condition often treatable with over-the-counter prescriptions. However, these human pathogens can greatly increase in severity and are not favorable for human health. Severe fungal infections such as cryptococcosis impact cellular immune functions by disrupting CD4+ lymphocytes. To combat these dreadful illnesses, researchers are studying the apoptosis mechanisms associated unique to fungi.
In 2000, a distinct family of caspases were discovered in fungi, protozoa, and some plants. These enzymes were coined as metacaspases (MCAs). MCAs are absent in humans and differ from orthologous human caspases. For this reason, inhibitors of metacaspases can be used as drug targets disrupting the life cycles of fungi and protozoa while not affecting the mammalian host. Examples of metacaspases can be found in Schizophyllum commune (S.commune) and Trypanosoma brucei (T. brucei) which are potential drug targets. Metacaspase inhibitors are designed to understand the cell’s state without the functioning enzyme to propose a step toward anti-fungal treatments. There are five metacaspases in Trypanosoma brucei noted as TbMCA1-5. One researcher, Maya Berg has already identified a compound that has shown promising metacaspase inhibition in Trypanosoma brucei. This competitive inhibitor demonstrated low micromolar activity with miniscule levels of cytotoxicity. Since metacaspases are found in protoza and fungi, we can apply known metacaspase inhibitor information of T.brucei to S.commune to demonstrate the inhibition of caspase activity in this organism. The Fox lab has identified eleven types of metacaspases in the multicellular fungus, S.commune. These enzymes, which include ScMC1 to ScM5, have been successfully purified. At the same time, the Kehlbeck lab has synthesized competitive inhibitors of S.commune metacaspases for the end goal of exploring the mechanism of action in these enzymes and potentially aid in the crystallization of the enzyme-substrate complex. It is hypothesized that the inhibitor will stabilize the enzyme structure to aid in crystallization.