Mechanism of Action
The putative mechanism of action of tetrandrine that underlies its potential use as a coronavirus disease 2019 (COVID-19) treatment is its ability to block the two-pore channel 2 (TPC2) in host cells and thus inhibit virus replication at low micromolar concentrations [7]. However, it has been reported also to block other targets, including L- and T-type calcium channels ([2], [8], and references therein).
Two-pore channels (TPCs) are intracellular calcium/cation channels located in the membranes of host endolysosomal compartments which SARS-CoV-2, the virus causing COVID-19 (and several other viruses) depend upon for egress from these organelles and replication. TPC2 has already been implicated in Middle East Respiratory Syndrome-Coronavirus (MERS-CoV) [9], Ebola virus (EBOV) [10], and Merkel cell polyoma virus (MCPyV) [11] infection as a key drug target.
There are specific TPC blocking agents (such as Ned-19, [12]), which have been shown to inhibit EBOV replication in vitro [10], but are currently only chemical tools, though they may engender drug candidates in the future. The different stereoisomers of Ned-19 can have different effects in vitro and their respective effects may differ according to tissue type [12;13].
However, many existing calcium channel antagonists block TPCs at relatively high concentrations (for example nifedipine, verapamil, etc. [14;15], and references therein), and there is evidence that such calcium channel blockers (CCBs) could be repurposed in viral illnesses [16;17]. While these are attractive candidates for repurposing due to their widespread use; their efficacy with respect to SARS-CoV-2 infection needs further investigation in the first instance.
Tetrandrine, while also not specific to TPC2 [2], shows greater efficacy in vitro against MERS-CoV than other CCBs [9]. It also decreased human coronavirus strain OC43 (HCoV-OC43) infection of MRC-5 human lung cells in vitro , with an inhibitory concentration (CC50) of 0.33 µM, lower than that of related alkaloids [18]. Critically, tetrandrine was found recently to be effective against SARS-CoV-2 in vitro [7].