Water-soluble tocopherol derivatives inhibit SARS-CoV-2 RNA-dependent RNA polymerase

Abstract

The recent emergence of a novel coronavirus, SARS-CoV-2, has led to the global pandemic of the severe disease COVID-19 in humans. While efforts to quickly identify effective antiviral therapies have focused largely on repurposing existing drugs, the current standard of care, remdesivir, remains the only authorized antiviral intervention of COVID-19 and provides only modest clinical benefits. Here we show that water-soluble derivatives of α-tocopherol have potent antiviral activity and synergize with remdesivir as inhibitors of the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). Through an artificial-intelligence-driven in silico screen and in vitro viral inhibition assay, we identified D-α-tocopherol polyethylene glycol succinate (TPGS) as an effective antiviral against SARS-CoV-2 and β-coronaviruses more broadly that also displays strong synergy with remdesivir. We subsequently determined that TPGS and other water-soluble derivatives of α-tocopherol inhibit the transcriptional activity of purified SARS-CoV-2 RdRp and identified affinity binding sites for these compounds within a conserved, hydrophobic interface between SARS-CoV-2 nonstructural protein 7 and nonstructural protein 8 that is functionally implicated in the assembly of the SARS-CoV-2 RdRp. In summary, we conclude that solubilizing modifications to α-tocopherol allow it to interact with the SARS-CoV-2 RdRp, making it an effective antiviral molecule alone and even more so in combination with remdesivir. These findings are significant given that many tocopherol derivatives, including TPGS, are considered safe for humans, orally bioavailable, and dramatically enhance the activity of the only approved antiviral for SARS-CoV-2 infection.

Drug Combinations as a First Line of Defense against Coronaviruses and Other Emerging Viruses

“…Two HCV protease inhibitors (boceprevir and narlaprevir) that blocked the SARS-CoV-2 C-like protease (3CL pro or M pro , a cysteine protease encoded by SARS-CoV-2 nsp5), were inhibitory on their own (EC 50 for boceprevir, 20 to 40 μM; EC 50 for narlaprevir, 8 to 37 μM, in Vero E6 cells) ( 75 , 89 , 102 ) but did not synergize with RDV ( 102 ). Experimental drugs, including brilacidin ( 88 ), a 3CL pro inhibitor ( 81 ), a RAD51 inhibitor ( 87 ), the natural product angeloylgomisin O ( 95 ), and a vitamin E derivative ( 97 ) have also been shown to synergize with RDV.…”

“… b Unless specified, drugs are FDA approved for the indicated conditions. Drugs in phase 1 (Ph1) for COVID-19 (CoV), e.g., reference 97 , are not listed. c Known or inferred target.…”

“…The reported synergies of the HCV drugs with RDV do demonstrate the potential utility of combinations targeting the SARS-CoV-2 polymerase and its proteases with DAAs (e.g., MPV plus Paxlovid [ 18 , 22 ]). Other new oral CoV protease inhibitors ( 22 , 112 , 113 , 125 – 127 ) and polymerase inhibitors ( 97 , 128 , 129 ) should also be considered if they have suitable C max /EC 50 ratios. Similarly, new TMPRSS2 inhibitors being explored ( 130 – 134 ) may have more suitable PK properties than camostat.…”

“…While approved drugs have the advantage that FDA guidance on the development of drug combinations allows for more rapid development ( https://www.fda.gov/media/80100 ), drugs that have passed human safety trials should also be considered as information about them becomes available. In this respect, it will be important to follow the development of AT-527 ( 128 ), other potential oral SARS-CoV-2 polymerase inhibitors ( 97 , 129 ) including oral forms of RDV ( 139 – 141 , 200 ) as well as the oral protease inhibitor GC-376 ( 102 , 125 ). As new oral/inhaled drugs with the same targets but better efficacy and PK become available, they should be analyzed as substitutes in previously characterized drug synergies.…”

Modulation of CD36‐mediated lipid accumulation and senescence by vitamin E analogs in monocytes and macrophages

“…It remains to be determined whether inhibition of proliferation by αTP is mediated by polymerase inhibition in a similar manner as described with RNA-dependent RNA polymerase (RdRp). 52…”