Repurposing the HCV NS3–4A protease drug boceprevir as COVID-19 therapeutics

Oerlemans, Rick; Ruiz-Moreno, Angel J.; Cong, Yirui; Kumar, Nilima Dinesh; Velasco-Velázquez, Marco A.; Neochoritis, Constantinos G.; Smith, Jolanda; Reggiori, Fulvio; Groves, Matthew R.; Dömling, Alexander

doi:10.1039/d0md00367k

Cited by 75 publications

(84 citation statements)

References 40 publications

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“…The viral inhibition was observed not only in translation and release but also in replication, which indicated that hypericin targeted the intracellular replication. In contrast to our previous γ-CoV study [ 23 ], we did not study the apoptosis and oxidative stress in PEDV or TGEV here due to the fact that the direct binding of hypericin onto 3CLpro was reported in SARS-CoV-2 [ 8 , 9 , 10 ], which guided us to validate whether hypericin target to TGEV and PEDV 3CLpro ( Figure 3 , Figures S2 and S3 ). As a consequence, the apoptosis and oxidative stress induction shown in the γ-CoV study might be a secondary effect of 3CLpro inhibition.…”

Section: Discussionmentioning

confidence: 73%

“…Fluorescence signals were captured with a Ti-S fluorescence microscope (Nikon, Tokyo, Japan). The percentage of viral infected cells was calculated by counting the cells with PEDV N-positive signal and dividing it by the number of DAPI-positive [ 10 ]. For each condition, we chose at least three views with more than 300 DAPI-positive cells and triplicated them to get the standard deviation.…”

Section: Methodsmentioning

confidence: 99%

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Hypericin Inhibit Alpha-Coronavirus Replication by Targeting 3CL Protease

Zhang

Chen

Zou

et al. 2021

Viruses

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The porcine epidemic diarrhea virus (PEDV) is an Alphacoronavirus (α-CoV) that causes high mortality in infected piglets, resulting in serious economic losses in the farming industry. Hypericin is a dianthrone compound that has been shown as an antiviral activity on several viruses. Here, we first evaluated the antiviral effect of hypericin in PEDV and found the viral replication and egression were significantly reduced with hypericin post-treatment. As hypericin has been shown in SARS-CoV-2 that it is bound to viral 3CLpro, we thus established a molecular docking between hypericin and PEDV 3CLpro using different software and found hypericin bound to 3CLpro through two pockets. These binding pockets were further verified by another docking between hypericin and PEDV 3CLpro pocket mutants, and the fluorescence resonance energy transfer (FRET) assay confirmed that hypericin inhibits the PEDV 3CLpro activity. Moreover, the alignments of α-CoV 3CLpro sequences or crystal structure revealed that the pockets mediating hypericin and PEDV 3CLpro binding were highly conserved, especially in transmissible gastroenteritis virus (TGEV). We then validated the anti-TGEV effect of hypericin through viral replication and egression. Overall, our results push forward that hypericin was for the first time shown to have an inhibitory effect on PEDV and TGEV by targeting 3CLpro, and it deserves further attention as not only a pan-anti-α-CoV compound but potentially also as a compound of other coronaviral infections.

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Section: Discussionmentioning

confidence: 73%

Section: Methodsmentioning

confidence: 99%

Hypericin Inhibit Alpha-Coronavirus Replication by Targeting 3CL Protease

Zhang

Chen

Zou

et al. 2021

Viruses

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“…We also hypothesized that these compounds, including PF-00835231, might prove to be effective against the mutants as well. Boceprevir, which is a protease inhibitor and was originally used to treat hepatitis, has been well studied to carry an inhibitory potential against the Mpro [24][25][26]. This compound was found to carry a very low affinity against the T190I whilst being the most active against the WT.…”

Section: Resultsmentioning

confidence: 99%

Is PF-00835231 a Pan-SARS-CoV-2 Mpro Inhibitor? A Comparative Study

et al. 2021

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The COVID-19 outbreak continues to spread worldwide at a rapid rate. Currently, the absence of any effective antiviral treatment is the major concern for the global population. The reports of the occurrence of various point mutations within the important therapeutic target protein of SARS-CoV-2 has elevated the problem. The SARS-CoV-2 main protease (Mpro) is a major therapeutic target for new antiviral designs. In this study, the efficacy of PF-00835231 was investigated (a Mpro inhibitor under clinical trials) against the Mpro and their reported mutants. Various in silico approaches were used to investigate and compare the efficacy of PF-00835231 and five drugs previously documented to inhibit the Mpro. Our study shows that PF-00835231 is not only effective against the wild type but demonstrates a high affinity against the studied mutants as well.

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“…7,8 Main protease (M pro ) of SARS-CoV-2 is some of the decisive factors in the infectious route of the virus; they have been reported as important targets for therapeutic strategies. 9 Because of discovery of new drugs require long time and expense, searching for new compounds from natural sources known with its high safety and applicability will be a good avenue to treat SARS-CoV-2. In order to quickly discovered lead compounds especially from the promising wild plants for clinical trials, virtual screening study was initiated to identify new drug targeting SARS-CoV-2.…”

Section: Introductionmentioning

confidence: 99%