Repurposing of CNS drugs to treat COVID-19 infection: targeting the sigma-1 receptor

Abstract

The novel coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The escalating number of SARS-CoV-2-infected individuals has conferred the viral spread with the status of global pandemic. However, there are no prophylactic or therapeutic drugs available on the market to treat COVID-19, although several drugs have been approved. Recently, two articles using the comparative viral-human protein-protein interaction map revealed that the sigma-1 receptor in the endoplasmic reticulum plays an important role in SARS-CoV-2 replication in cells. Knockout and knockdown of SIGMAR1 (sigma-1 receptor, encoded by SIGMAR1) caused robust reductions in SARS-CoV-2 replication, which indicates that the sigma-1 receptor is a key therapeutic target for SARS-CoV-2 replication. Interestingly, a recent clinical trial demonstrated that treatment with the antidepressant fluvoxamine, which has a high affinity at the sigma-1 receptor, could prevent clinical deterioration in adult outpatients infected with SARS-CoV-2. In this review, we discuss the brief history of the sigma-1 receptor and its role in SARS-CoV-2 replication in cells. Here, we propose repurposing of traditional central nervous system (CNS) drugs that have a high affinity at the sigma-1 receptor (i.e., fluvoxamine, donepezil, ifenprodil) for the treatment of SARS-CoV-2-infected patients. Finally, we discussed the potential of other CNS candidates such as cutamesine and arketamine.

Keywords: Endoplasmic reticulum; Replication; Sigma-1 receptor.

Fig. 1

Chemical structure of fluvoxamine, donepezil, and ifenprodil

Fig. 2

Role of the sigma-1 receptor in the ER and ER stress during the replication cycle of SARS-CoV-2 in cells. SARS-CoV-2 binds to the ACE2 (angiotensin-converting enzyme 2) receptor on the surface of cells via spike proteins, which subsequently triggers endocytosis. Subsequent SARS-CoV-2 replication takes place in an ER-derived intermediate compartment of the ER-Golgi. It has been suggested that ER stress due to the replication of SARS-CoV-2 may contribute to inflammatory events (i.e., cytokine storm), which results in severe symptoms of acute respiratory distress syndrome, accompanied by high mortality. The sigma-1 receptor in the ER plays a key role in the replication of SARS-CoV-2 in cells [41, 42]. A slight modification is shown in this figure, from Zhang et al. [1]

Fig. 3

Proposed scheme for prophylactic effects of sigma-1-receptor agonists in the treatment of SARS-CoV-2-infected patients. Recent studies show that sigma-1-receptor ligands attenuate SARS-CoV-2 replication [41, 42]. Via sigma-1 receptor chaperone activity, traditional CNS compounds (i.e., fluvoxamine, donepezil, ifenprodil) with potent sigma-1-receptor agonism may attenuate ER stress due to SARS-CoV-2 replication in cells, thus resulting in a blockade against inflammatory events (i.e., cytokine storm). Thus, early treatment using sigma-1-receptor agonists may block or delay clinical deterioration in individuals with SARS-CoV-2 infection. A slight modification is shown in Fig. 2, from Zhang et al. [1]