Abstract
Emerging evidence hints in favor of a life-threatening link between severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) and the cardiovascular system. SARS-CoV-2 may result in dramatic cardiovascular complications, whereas the severity of COronaVIrus Disease 2019 (COVID-19) and the incidence of fatalities tend to increase in patients with pre-existing cardiovascular complications. SARS-CoV-2 is internalized into the host cells by endocytosis and may then escape the endolysosomal system via endosomes. Two-pore channels drive endolysosomal trafficking through the release of endolysosomal Ca2+. Recent evidence suggested that the pharmacological inhibition of TPCs prevents Ebola virus and Middle East Respiratory Syndrome COronaVirus (MERS-CoV) entry into host cells. In this perspective, we briefly summarize the biophysical and pharmacological features of TPCs, illustrate their emerging role in the cardiovascular system, and finally present them as a reliable target to treat cardiovascular complications in COVID-19 patients.
Highlights
The dramatic outbreak of the COronaVIrus Disease 2019 (COVID-19), which is caused by the novel severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), is imposing an unmet medical need to the scientific community
We discuss the possibility of targeting two-pore channels (TPCs), which are crucial to endocytosis and EL trafficking (Chao et al, 2020; Vassileva et al, 2020), to interfere with SARS-CoV-2 entry into cardiovascular cells
EBOV infection in vitro was strongly repressed by blocking TPCs with NED-19 and with three structurally distinct inhibitors of L-type voltage-gated Ca2+ channels, i.e., verapamil, diltiazem, and nimodipine (Sakurai et al, 2015). These findings suggested that CaV antagonists, which have been approved by the Food and Drug Administration (FDA) for the treatment of multiple cardiovascular disorders (Godfraind, 2017; Oparil et al, 2018), could represent an alternative strategy to combat Ebola hemorrhagic fever
Summary
The dramatic outbreak of the COronaVIrus Disease 2019 (COVID-19), which is caused by the novel severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), is imposing an unmet medical need to the scientific community. Measurement of PI(3,5)P2-evoked lysosomal currents, NAADP-induced Ca2+ release and single-channel activity, revealed that FDA-approved dopamine antagonists, such as pimozide and fluphenazine, and selective estrogen receptor modulators, such as clomiphene and raloxifene, were able to target TPC2 by plugging the channel pore (Penny et al, 2019) These novel inhibitors of TPC2 effectively reduced EBOV infection in vitro (Penny et al, 2019). The role of EL Ca2+ release in mediating this process was further suggested by the inhibitory effect on MERS-CoV infectivity of chloroquine and the weak base ammonium chloride (NH4Cl) (Gunaratne et al, 2018a) These drugs inhibit cathepsin activity and, prevent S protein activation, by neutralizing EL pH (Chan et al, 2015). Its efficacy against viral infection endorses the pharmacological inhibition of TPC-mediated EL Ca2+ release as a promising therapeutic option
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