Statins: Could an old friend help in the fight against COVID-19?

Abstract

The COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has overwhelmed healthcare systems requiring the rapid development of treatments, at least, to reduce COVID-19 severity. Drug repurposing offers a fast track. Here, we discuss the potential beneficial effects of statins in COVID-19 patients based on evidence that they may target virus receptors, replication, degradation, and downstream responses in infected cells, addressing both basic research and epidemiological information. Briefly, statins could modulate virus entry, acting on the SARS-CoV-2 receptors, ACE2 and CD147, and/or lipid rafts engagement. Statins, by inducing autophagy activation, could regulate virus replication or degradation, exerting protective effects. The well-known anti-inflammatory properties of statins, by blocking several molecular mechanisms, including NF-κB and NLRP3 inflammasomes, could limit the "cytokine storm" in severe COVID-19 patients which is linked to fatal outcome. Finally, statin moderation of coagulation response activation may also contribute to improving COVID-19 outcomes. LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID-19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc.

FIGURE 1

SARS‐CoV‐2 complete infectious virion. The RNA genome encodes a spike protein (SP), an envelope protein (EP), a membrane protein (MP), and a nucleoprotein (NP). The spike protein is the most important surface membrane protein of the SARS‐CoV‐2

FIGURE 2

Schematic summary of SARS‐CoV‐2 entry into host cells, replication, effect on host cells, and postulated effects of statins. ACE2 and CD147 are located in the plasma membrane, associated with lipid rafts, and can act as SARS‐CoV‐2 receptors. Statins, by inhibiting cholesterol synthesis, can modify the composition of lipid rafts. Statins can also down‐regulate CD147 expression and its translocation to the cell surface. Autophagy in host cells is altered during SARS‐CoV‐2 infection, by a mechanism that involves SKP2 up‐regulation and subsequent BECN1 degradation. Statins decrease SKP2 levels and induce BECN1 and LC3 II synthesis, which trigger autophagy activation. Another process modulated by SARSCoV‐2 is the activation of the NF‐κB pathway leading to proinflammatory cytokine synthesis, including IL‐6, and NLRP3 inflammasome activation. Statins can down‐regulate NF‐κB pathway activation, proinflammatory cytokine synthesis, and NLRP3 inflammasome activation. Anti‐thrombotic effects of statins by TF modulation could also be beneficial in COVID‐19 patients. Purple, discontinuous lines: viral entry and release. Black lines: cell processes. Green lines: positive regulation of the process. Red lines: negative regulation of the process. Continuous green or red lines: process regulated by statins. Discontinuous green or red lines: process regulated by virus. Viral proteins: EP, envelope protein; NP, nucleocapsid protein; MP, membrane protein; SP: spike protein. ^*Targets of specific ongoing clinical trials against COVID‐19