Two-pore Channel Protein 2 as a Novel Broad-Spectrum Host-Acting Antiviral Target

Abstract

In the aftermath of the COVID-19 pandemic, the need for development of new broad-spectrum host-acting antivirals (HAV) has become more apparent than ever before. Given that there remain nearly 20 human viruses that are WHO priority pathogens who have the potential to be just as deadly as SARS-CoV-2, research has shifted focus to finding host targets that are widely used by human viruses during their lifecycle for HAV development. The two-pore-channel 2 protein (TPC2) may be such a target. TPC2 is a voltage gated calcium ion channel found ubiquitously in all host cells, predominantly in late endosome and lysosome-related organelles. The main function of TPC2 is to control intracellular calcium mobilization from endolysosomal bodies, regulating calcium efflux from these acidic compartments. Due to the nature of TPC2’s positioning within the cell as a master regulator of cytosolic calcium signaling, it has been predicted that inhibiting TPC2 may negatively affect viruses whose entry and escape pathways are calcium dependent. Building of this notion, here in this article we explore the mechanisms behind the potential of TPC2 as a broad spectrum HAV target. We first delve into previous literature to confirm if blocking TPC2 has antiviral activity via regulation of the endolysosomal pathway, which is often hijacked by WHO priority viruses such as Ebola, MERS-CoV and SARS-CoV-2 for viral entry into the cytoplasm. In this realm, we also briefly look at the existing approaches of TPC2 inhibition and its applicability in a multidrug regimen. Next, we move to investigate if TPC2 inhibition can affect other mechanisms important to the general viral lifecycle beyond just the endolysosomal pathway, such as furin mediated viral glycoprotein processing or exosome biogenesis. Answering this question would ultimately allow us to also delineate the broad-spectrum nature or lack thereof for TPC2 as an HAV target. By examining the mechanisms by which TPC2 interacts with and influences the viral lifecycle of different WHO priority pathogens, we can better understand and appreciate its putative action as a broad-spectrum HAV target, giving credence to its development as a novel HAV therapy.