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

Eur Arch Psychiatry Clin Neurosci. 2021 Mar;271(2):249-258. doi: 10.1007/s00406-020-01231-x. Epub 2021 Jan 5.

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.

Publication types

  • Review

MeSH terms

  • Animals
  • COVID-19 / drug therapy*
  • Central Nervous System Agents / therapeutic use*
  • Drug Repositioning*
  • Gene Knockout Techniques
  • Humans
  • Receptors, sigma / drug effects*
  • Receptors, sigma / genetics

Substances

  • Central Nervous System Agents
  • Receptors, sigma
  • sigma-1 receptor