All-Trans Retinoic Acid Exhibits Antiviral Effect against SARS-CoV-2 by Inhibiting 3CLpro Activity

Abstract

The pandemic of COVID-19 caused by SARS-CoV-2 continues to spread despite the global efforts taken to control it. The 3C-like protease (3CLpro), the major protease of SARS-CoV-2, is one of the most interesting targets for antiviral drug development because it is highly conserved among SARS-CoVs and plays an important role in viral replication. Herein, we developed high throughput screening for SARS-CoV-2 3CLpro inhibitor based on AlphaScreen. We screened 91 natural product compounds and found that all-trans retinoic acid (ATRA), an FDA-approved drug, inhibited 3CLpro activity. The 3CLpro inhibitory effect of ATRA was confirmed in vitro by both immunoblotting and AlphaScreen with a 50% inhibition concentration (IC50) of 24.7 ± 1.65 µM. ATRA inhibited the replication of SARS-CoV-2 in VeroE6/TMPRSS2 and Calu-3 cells, with IC50 = 2.69 ± 0.09 µM in the former and 0.82 ± 0.01 µM in the latter. Further, we showed the anti-SARS-CoV-2 effect of ATRA on the currently circulating variants of concern (VOC); alpha, beta, gamma, and delta. These results suggest that ATRA may be considered as a potential therapeutic agent against SARS-CoV-2.

Utilizing the Crosstalk Among Minocycline, Chicoric Acid, 13-Cis Retinoic Acid(Aerosolized) and Vitamin D as a Potent Quadrate Therapy for treating coinfection with Multidrug-resistant TB and COVID-19 . A double-edged sword Clinical Study

“…It has been documented that isotretinoin is a protease inhibitors and can be a taken as a target therapy in COVID-19 (42). After our clinical trial many studies con rmed our suggestion and found that isotretinoin and all trans retinoic acid could protect individuals against COVID-19 complication (43,44,45,46,47,48).…”

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

“…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.…”

COVID-19 in 2021

“…Using SARS-CoV-2 for testing combination therapy with remdesivir in Vero-E6 and Calu-3 cells, circlesonide, nelfinavir, and camostat were identified as potential therapeutic options against MERS-CoV, which also can provide the basis for COVID-19 therapeutics. In another approach, high throughput screening of SARS-CoV-2 3C-like protease (3CLpro) inhibitor was conducted based on the AlphaScreen technology [ 2 ]. Screening of 91 natural product compounds identified all-trans retinoic acid (ATRA), which inhibited SARS-CoV-2 replication in Vero E6 and Calu-3 cells.…”