In Vitro Assessment of the Antiviral Activity of Ketotifen, Indomethacin and Naproxen, Alone and in Combination, against SARS-CoV-2

Kiani, Pantea; Scholey, Andrew; Dahl, Thomas; McMann, Lauren; Iversen, Jacqueline M.; Verster, Joris C.

doi:10.3390/v13040558

Cited by 27 publications

(24 citation statements)

References 43 publications

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“…The viral RNA polymerase inhibitor remdesivir (RMV) was included as a positive control of inhibition [ 45 ]. As reported in Table 1 , INM inhibited the replication of SARS-CoV-2 with an Effective Concentration (EC 50 ) of 94.9 μM, a value similar to those already reported for SARS-CoV and SARS-CoV-2 [ 26 , 28 ]. Among the four tested PROTACs, while the introduction of a short aliphatic as well as a PEGylated linker did not result in active PROTACs, compounds 3 (bearing a 6-methylene units linker) and 5 (bearing a piperazine-based linker) resulted the most potent compounds showing (EC 50 values of 18.1 μM and 21.5 μM, respectively.…”

Section: Resultssupporting

confidence: 84%

“…Gordon and co-workers also found that COVID-19 patients treated with INM were less likely to require hospitalization than those treated with other anti-inflammatory drugs that do not target PGES-2, providing a connection between proteomics study and clinical data [ 29 ]. However, it is worth noting that the anti-SARS-CoV-2 potency of INM is limited in infected cells, being in the range of ∼100 μM (this study and ref [ 28 ]). Taking this into account, we hypothesized that the exploitation of INM for PROTAC design could result in an enhancement of antiviral activity, since the degradation of the target PGES-2 could be obtained in addition to enzymatic inhibition and potentiate the antiviral effect.…”

Section: Introductionmentioning

confidence: 72%

“…This new therapeutic indication was validated by transcriptomic and proteomic data in SARS-CoV-2-infected human cells and data from ongoing clinical trials [ 20 ]. INM was also evaluated in vitro against SARS-CoV-2 alone or in combination with ketotifene [ 28 ]. Although in a 4-day cytopathic effect protection assay INM did not exhibit any antiviral activity (EC 50 > 400 μM, Vero E6 cells), its evaluation in a virus yield reduction assay under reduced rounds of virus replication (48 h) showed an inhibition of SARS-CoV-2 replication with an EC 50 of 100.1 μM (in infected Vero E6 cells) [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

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Indomethacin-based PROTACs as pan-coronavirus antiviral agents

Desantis

Mercorelli

Celegato

et al. 2021

European Journal of Medicinal Chemistry

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Indomethacin (INM), a well-known non-steroidal anti-inflammatory drug, has recently gained attention for its antiviral activity demonstrated in drug repurposing studies against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Although the mechanism of action of INM is not yet fully understood, recent studies have indicated that it acts at an early stage of the coronaviruses (CoVs) replication cycle. In addition, a proteomic study reported that the anti-SARS-CoV-2 activity of INM could be also ascribed to its ability to inhibit human prostaglandin E synthase type 2 (PGES-2), a host protein which interacts with the SARS-CoV-2 NSP7 protein. Although INM does not potently inhibit SARS-CoV-2 replication in infected Vero E6 cells, here we have explored for the first time the application of the Proteolysis Targeting Chimeras (PROTACs) technology in order to develop more potent INM-derived PROTACs with anti-CoV activity. In this study, we report the design, synthesis, and biological evaluation of a series of INM-based PROTACs endowed with antiviral activity against a panel of human CoVs, including different SARS-CoV-2 strains. Two PROTACs showed a strong improvement in antiviral potency compared to INM. Molecular modelling studies support human PGES-2 as a potential target of INM-based antiviral PROTACs, thus paving the way toward the development of host-directed anti-CoVs strategies. To the best of our knowledge, these PROTACs represent the first-in-class INM-based PROTACs with antiviral activity and also the first example of the application of PROTACs to develop pan-coronavirus agents.

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Section: Resultssupporting

confidence: 84%

Section: Introductionmentioning

confidence: 72%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Indomethacin-based PROTACs as pan-coronavirus antiviral agents

Desantis

Mercorelli

Celegato

et al. 2021

European Journal of Medicinal Chemistry

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“…Pseudotyped viruses with B.1.617 and B.1.618 S protein when exposed to convalescent sera from patients infected with WT SARS-CoV-2, showed a 2.3-fold and 2.8-fold resistance to neutralization compared to viruses with S (WT) protein respectively (Tada et al, 2021 (Liu et al, 2021a). As the search for neutralizing antibodies quickly arose to retaliate against the pandemic, due to the drastic immune reactions observed in the lung tissues together with the cytokine storm syndrome, some focus was given to repurposing and testing antiviral drugs found to have antiviral activity in cell culture experiments (Kiani et al, 2021). Cytokines with known antiviral effect including interferons were also evaluated (Haji Abdolvahab et al, 2021).…”

Section: Monoclonal Antibodies Therapymentioning

confidence: 99%

The rapid adaptation of SARS-CoV-2–rise of the variants: transmission and resistance

Soh

Kim

et al. 2021

J Microbiol.

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The causative factor of COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is continuously mutating. Interestingly, identified mutations mainly occur in the spike (S) protein which interacts with the ACE2 receptor and is cleaved via serine protease TMPRSS2. Some mutated strains are becoming dominant in various parts of the globe because of increased transmissibility as well as cell entry efficacy. Remarkably, the neutralizing activity of monoclonal antibodies, convalescent sera, and vaccines against the variants has been reported to be significantly reduced. Therefore, the efficacy of various monoclonal antibodies therapy and vaccines against these variants is becoming a great global concern. We herein summarize the current status of SARS-CoV-2 with gears shifted towards the recent and most common genetic variants in relation to transmission, neutralizing activity, and vaccine efficacy.

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“…Some recent papers have studied the antiviral activity of NSAIDs against SARS-CoV-2 protein. For example, they showed that the anti-viral activity of Ketotifen, Indomethacin, and Naproxen could reduce SARS-CoV-2 replication [ [10] , [11] , [12] ]. Furthermore, it was shown that indomethacin exerts anti-SARS-CoV activity in both in vivo and in vitro models [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Potential inhibitors of the main protease of SARS-CoV-2 and modulators of arachidonic acid pathway: Non-steroidal anti-inflammatory drugs against COVID-19

Sisakht

Solhjoo

Mahmoodzadeh

et al. 2021

Computers in Biology and Medicine

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The main protease of SARS-CoV-2 is one of the key targets to develop and design antiviral drugs. There is no general agreement on the use of non-steroidal anti-inflammatory drugs (NSAIDs) in COVID-19. In this study, we investigated NSAIDs as potential inhibitors for chymotrypsin-like protease (3CLpro) and the main protease of the SARS-CoV-2 to find out the best candidates, which can act as potent inhibitors against the main protease. We also predicted the effect of NSAIDs on the arachidonic pathway and evaluated the hepatotoxicity of the compounds using systems biology techniques. Molecular docking was conducted via AutoDock Vina to estimate the interactions and binding affinities between selected NSAIDs and the main protease. Molecular docking results showed the presence of 10 NSAIDs based on lower binding energy (kcal/mol) toward the 3CLpro inhibition site compared to the co-crystal native ligand Inhibitor N3 (−6.6 kcal/mol). To validate the docking results, molecular dynamic (MD) simulations on the top inhibitor, Talniflumate, were performed. To obtain differentially-expressed genes under the 27 NSAIDs perturbations, we utilized the L1000 final Z-scores from the NCBI GEO repository (GSE92742). The obtained dataset included gene expression profiling signatures for 27 NSAIDs. The hepatotoxicity of NSAIDs was studied by systems biology modeling of Disturbed Metabolic Pathways. This study highlights the new application of NSAIDs as anti-viral drugs used against COVID-19. NSAIDs may also attenuate the cytokine storm through the downregulation of inflammatory mediators in the arachidonic acid pathway.

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In Vitro Assessment of the Antiviral Activity of Ketotifen, Indomethacin and Naproxen, Alone and in Combination, against SARS-CoV-2

Cited by 27 publications

References 43 publications

Indomethacin-based PROTACs as pan-coronavirus antiviral agents

Indomethacin-based PROTACs as pan-coronavirus antiviral agents

The rapid adaptation of SARS-CoV-2–rise of the variants: transmission and resistance

Potential inhibitors of the main protease of SARS-CoV-2 and modulators of arachidonic acid pathway: Non-steroidal anti-inflammatory drugs against COVID-19

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