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].