Gallium maltolate has in vitro antiviral activity against SARS-CoV-2 and is a potential treatment for COVID-19

Abstract

Background Gallium has demonstrated strong anti-inflammatory activity in numerous animal studies, and has also demonstrated direct antiviral activity against the influenza A H1N1 virus and the human immunodeficiency virus (HIV). Gallium maltolate (GaM), a small metal-organic coordination complex, has been tested in several Phase 1 clinical trials, in which no dose-limiting or other serious toxicity was reported, even at high daily oral doses for several months at a time. For these reasons, GaM may be considered a potential candidate to treat coronavirus disease 2019 (COVID-19), which is caused by the SARS-CoV-2 virus and can result in severe, sometimes lethal, inflammatory reactions. In this study, we assessed the ability of GaM to inhibit the replication of SARS-CoV-2 in a culture of Vero E6 cells. Methods The efficacy of GaM in inhibiting the replication of SARS-CoV-2 was determined in a screening assay using cultured Vero E6 cells. The cytotoxicity of GaM in uninfected cells was determined using the Cell Counting Kit-8 (CCK-8) colorimetric assay. Results The results showed that GaM inhibits viral replication in a dose-dependent manner, with the concentration that inhibits replication by 50% (EC50) being about 14 µM. No cytotoxicity was observed at concentrations up to at least 200 µM. Conclusion The in vitro activity of GaM against SARS-CoV-2, together with GaM’s known anti-inflammatory activity, provide justification for testing GaM in COVID-19 patients.

Exploring the Role of Heavy Metals and Their Derivatives on the Pathophysiology of COVID-19

“…Vanadium can stimulate the activation of T cells [116], and bismuth has an inhibitory effect on helix unwinding and ATPase activity of SARS-CoV-2 nsp13 [27], so these metals might be useful in the treatment of COVID-19. About gallium there are two ideas, some studies believe that gallium has an anti-inflammatory and antiviral activity against SARS-CoV-2 and inhibits viral replication [119][120][121][122][123], but other studies believe that there is no relation between gallium uptake and COVID-19 related disorders [118]. Palladium and some Schiff base complexes of titanium have an affinity to the main protease of SARS-CoV-2, so they may be useful in vaccine production [127,128].…”

“…And at last, it is observed that gallium has an anti-inflammatory effect which is effective against hyperinflammatory signs observed in harsh cases of COVID-19 patients which is similar to septic shock [121,122]. GaM inhibited replication of virus dose dependently with a concentration of 14 μM, which replication inhibited by 50% [123].…”

Development of Metal Complexes for Treatment of Coronaviruses

“…At doses up to 200 mM, the gallium maltolate was not hazardous to the cells (the function of cells at 200 mM was 109(3)% compared with the control cells) ( Figure S6 ). [ 128 ] The EC50 data was estimated by an inhibitor vs. balanced response, movable slope equation: Y = 100/(1 + 10exp((LogEC50 − X) × HillSlope)). …”

Potential metal-related strategies for prevention and treatment of COVID-19

“…At present, two methods are used to discover potential metal-based drugs for COVID-19: repurposing existing medications and developing new drugs [ 27 , 28 ]. These metallodrugs might directly inhibit virus replication [ 68 , 69 ], prevent viruses from entering cells [ 63 ], or inhibit the activity of critical enzymes in the process of virus replication [ 34 – 36 , 70 , 71 ]. Furthermore, the combination of antiviral drugs and metals can be more effective.…”

“…Pectol et al [ 104 ] proved that dinitroso-iron complexes (DNICs) could be used as inhibitors of SARS-CoV-2 M pro through computer prediction and external studies. In addition, Bernstein and Zhang [ 69 ] used gallium maltolate (GaM) to treat SARS-CoV-2-infected Vero E6 cells to evaluate the antiviral ability. Its ability to prevent virus replication has been proven, and its efficacy is related to dosage.…”