Metacaspases: Potential Drug Target Against Protozoan Parasites

Abstract

Among the numerous strategies/targets for controlling infectious diseases, parasites-derived proteases receive prime attention due to their essential contribution to parasite growth and development. Parasites produce a broad array of proteases, which are required for parasite entry/invasion, modification/degradation of host proteins for their nourishment, and activation of inflammation that ensures their survival to maintain infection. Presently, extensive research is focused on unique proteases termed as “metacaspases” (MCAs) in relation to their versatile functions in plants and non-metazoans. Such unique MCAs proteases could be considered as a potential drug target against parasites due to their absence in the human host. MCAs are cysteine proteases, having Cys-His catalytic dyad present in fungi, protozoa, and plants. Studies so far indicated that MCAs are broadly associated with apoptosis-like cell death, growth, and stress regulation in different protozoa. The present review comprises the important research outcomes from our group and published literature, showing the variable properties and function of MCAs for therapeutic purpose against infectious diseases.

Endoplasmic reticulum localized TMEM33 domain‐containing protein is crucial for all life cycle stages of the malaria parasite

“…Though we have only evaluated the level of BiP mRNA, the upregulation in its expression can still be considered as an indicator of ER stress in Pbtmem33(−) parasites (Figure S2b). Since ER stress results in the activation of ERAD and UPR, which in turn regulates cell death pathways like apoptosis and autophagy (Peng et al., 2021), we checked the mRNA expression of autophagy (ATGs) and apoptosis (metacaspases) related genes (Kamil et al., 2019; Kamil, Atmaca, et al., 2022; Vandana et al., 2019). Our preliminary qPCR data showed that TMEM33 deletion results in the generation of ER stress which upregulated the expression of autophagy‐related genes in the malaria parasites (Figure S2c); however, no effect was observed in the expression of apoptosis marker genes (Figure S2d).…”

Design and synthesis of novel glycyrrhetinic acid-triazole derivatives that exert anti-plasmodial activity inducing mitochondrial-dependent apoptosis in Plasmodium falciparum

“…[73][74][75] Plasmodium species are reported to possess caspases like genes, the metacaspases, which induce apoptosis-like death. [76][77][78] Exposure to compound-17 increased the activity of caspase-3, a crucial enzyme of apoptosis. The apoptosis was confirmed by measuring markers such as DNA damage (TUNEL assay) and phosphatidylserine externalisation assay.…”

Mediterranean Diet: Lipids, Inflammation, and Malaria Infection

“…Artemisinin-based combination therapies are the gold standard treatment, when correctly employed [24]. Considerable effort has been made for the development of new malaria treatment as the potential use of "metacaspases", the unique proteases absent in humans [30]. Tafenoquine was recently registered to treat Plasmodium vivax.…”