Inhibition of Severe Acute Respiratory Syndrome Coronavirus 2 main protease by tafenoquinein vitro

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing the current pandemic, coronavirus disease 2019 (COVID-19), has taken a huge toll on human lives and the global economy. Therefore, effective treatments against this disease are urgently needed. Here, we established a fluorescence resonance energy transfer (FRET)-based high-throughput screening platform to screen compound libraries to identify drugs targeting the SARS-CoV-2 main protease (Mpro), in particular those which are FDA-approved, to be used immediately to treat patients with COVID-19. Mpro has been shown to be one of the most important drug targets among SARS-related coronaviruses as impairment of Mpro blocks processing of viral polyproteins which halts viral replication in host cells. Our findings indicate that the anti-malarial drug tafenoquine (TFQ) induces significant conformational change in SARS-CoV-2 Mpro and diminishes its protease activity. Specifically, TFQ reduces the alpha-helical content of Mpro, which converts it into an inactive form. Moreover, TFQ greatly inhibits SARS-CoV-2 infection in cell culture system. Hence, the current study provides a mechanistic insight into the mode of action of TFQ against SARS-CoV-2 Mpro. Moreover, the low clinical toxicity of TFQ and its strong antiviral activity against SARS-CoV-2 should warrant further testing in clinical trials.

Drug Repurposing Against SARS-CoV-1, SARS-CoV-2 and MERS-CoV

“…The maximal plasmatic concentration of tafenoquine, used for Plasmodium vivax infections, exhibited interindividual variability, its bioavailability being greatly influenced by high-fat meals. Preliminary studies demonstrated that tafenoquine had an anti-SARS-CoV-2 activity in Vero E6 cells in two studies that found an EC 50 from 2.5 to 16 μM [ 133 , 134 ].…”

Recent advances in developing small-molecule inhibitors against SARS-CoV-2

“…4 ( 10 ) Clofazimine In vivo 0.31 ‒ Preclinical 68 Replication inhibitors Target 3CLpro Fig. 5 ( 11 ) Tafenoquine In vitro 2.5 ‒ Preclinical 72 In vitro ∼ 2.6 ≥ 50 Preclinical 73 Fig. 5 ( 12 ) 12 In vitro 0.25 ± 0.15 ＞100 Preclinical 74 Fig.…”

“…Chen and his colleagues 72 established a HTS platform based on fluorescence resonance energy transfer (FRET) to identify drugs targeting the SARS-CoV-2 3CLpro from compound libraries, especially FDA-approved drugs, to be used immediately to treat patients with COVID-19. Their findings indicate that the 8-aminoquinoline antimalarial drug tafenoquine [ Fig.…”

Beyond the vaccines: a glance at the small molecule and peptide-based anti-COVID19 arsenal

“…Resultantly, 80 (tafenoquine), an antimalarial drug, was found to be endowed with the potential to exert conformational change in SARS-CoV-2 Mpro, thereby diminishing the protease activity. Also, the drug significantly inhibited SARS-CoV-2 infection in the cell culture system (IC 50 = 2.5 µmol/L) [ 102 ]. In another study, 80 (Tafenoquine) was found to be more potent than hydroxychloroquine in inhibiting SARS-CoV-2 in VERO E6 cells (Fig.…”