Repurposing existing drugs: identification of SARS-CoV-2 3C-like protease inhibitors

Chiou, Wei Chung; Hsu, Meng Shiuan; Chen, Yun Ti; Yang, Jinn-Moon; Tsay, Yeou Guang; Huang, Haoping; Huang, Cheng

doi:10.1080/14756366.2020.1850710

Cited by 33 publications

(34 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Naproxen’s mechanism of action demonstrated here involved the inhibition of N oligomerization associated with its antiviral effect. Nevertheless, we cannot rule out that naproxen may bind other viral targets, such as the viral 3C-like protease, as suggested from modeling studies and experimental determination of an IC50 of 3.45 µM [ 39 ]. Indeed, during replication and viral particle assembly, viral proteases cleave polyproteins expressed by the virus to produce a number of essential Non Structural Proteins (NSPs); hence, protease-inhibitors are a popular class of antiviral candidates.…”

Section: Discussionmentioning

confidence: 99%

Antiviral Properties of the NSAID Drug Naproxen Targeting the Nucleoprotein of SARS-CoV-2 Coronavirus

et al. 2021

View full text Add to dashboard Cite

There is an urgent need for specific antiviral treatments directed against SARS-CoV-2 to prevent the most severe forms of COVID-19. By drug repurposing, affordable therapeutics could be supplied worldwide in the present pandemic context. Targeting the nucleoprotein N of the SARS-CoV-2 coronavirus could be a strategy to impede viral replication and possibly other essential functions associated with viral N. The antiviral properties of naproxen, a non-steroidal anti-inflammatory drug (NSAID) that was previously demonstrated to be active against Influenza A virus, were evaluated against SARS-CoV-2. Intrinsic fluorescence spectroscopy, fluorescence anisotropy, and dynamic light scattering assays demonstrated naproxen binding to the nucleoprotein of SARS-Cov-2 as predicted by molecular modeling. Naproxen impeded recombinant N oligomerization and inhibited viral replication in infected cells. In VeroE6 cells and reconstituted human primary respiratory epithelium models of SARS-CoV-2 infection, naproxen specifically inhibited viral replication and protected the bronchial epithelia against SARS-CoV-2-induced damage. No inhibition of viral replication was observed with paracetamol or the COX-2 inhibitor celecoxib. Thus, among the NSAID tested, only naproxen combined antiviral and anti-inflammatory properties. Naproxen addition to the standard of care could be beneficial in a clinical setting, as tested in an ongoing clinical study.

show abstract

Section: Discussionmentioning

confidence: 99%

Antiviral Properties of the NSAID Drug Naproxen Targeting the Nucleoprotein of SARS-CoV-2 Coronavirus

et al. 2021

View full text Add to dashboard Cite

show abstract

“…This finding affords a further validation of the overall predictive power of the reported VS strategies, especially considering that the inhibition activity of several SARS-CoV 3CL-Pro inhibitors against the SARS-CoV-2 3CL-Pro enzyme was experimentally confirmed (as discussed above for TG-0205221 analogues. Among the other 102 molecules, there are 37 compounds that are known inhibitors of SARS-CoV 3CL-Pro but with pIC50 < 5, and 17 known inhibitors of the main proteases of other viruses (such as norovirus and HIV), and these compounds represent a further confirmation of the efficacy of the performed VS campaigns, since some of the retrieved hits (rupintrivir [31], saquinavir [32], and lopinavir [33]) were experimentally confirmed as promising inhibitors of SARS-CoV-2 3CL-Pro. Finally, among the other common molecules, cobicistat [34] and galloyl analogues [35] were identified as SARS-CoV-2 3CL-Pro inhibitors.…”

Section: Analysis Of the Best Rankingsmentioning

confidence: 99%

Combining Different Docking Engines and Consensus Strategies to Design and Validate Optimized Virtual Screening Protocols for the SARS-CoV-2 3CL Protease

et al. 2021

View full text Add to dashboard Cite

The 3CL-Protease appears to be a very promising medicinal target to develop anti-SARS-CoV-2 agents. The availability of resolved structures allows structure-based computational approaches to be carried out even though the lack of known inhibitors prevents a proper validation of the performed simulations. The innovative idea of the study is to exploit known inhibitors of SARS-CoV 3CL-Pro as a training set to perform and validate multiple virtual screening campaigns. Docking simulations using four different programs (Fred, Glide, LiGen, and PLANTS) were performed investigating the role of both multiple binding modes (by binding space) and multiple isomers/states (by developing the corresponding isomeric space). The computed docking scores were used to develop consensus models, which allow an in-depth comparison of the resulting performances. On average, the reached performances revealed the different sensitivity to isomeric differences and multiple binding modes between the four docking engines. In detail, Glide and LiGen are the tools that best benefit from isomeric and binding space, respectively, while Fred is the most insensitive program. The obtained results emphasize the fruitful role of combining various docking tools to optimize the predictive performances. Taken together, the performed simulations allowed the rational development of highly performing virtual screening workflows, which could be further optimized by considering different 3CL-Pro structures and, more importantly, by including true SARS-CoV-2 3CL-Pro inhibitors (as learning set) when available.

show abstract

“…Chiou and coworkers [ 77 ] have reported that raloxifene is a potent inhibitor of SARS−CoV−2 M pro (IC 50 = 5.61 μmol/L). It is known that part of the ERM biological effect lies in their interaction with ER.…”

Section: Erms and Estrogens As Inhibitors Of Sars−cov−2 Proteasesmentioning

confidence: 99%

Estrogen Receptor Modulators in Viral Infections Such as SARS−CoV−2: Therapeutic Consequences

Abramenko

Vellieux

Tesařová

et al. 2021

IJMS

View full text Add to dashboard Cite

COVID−19 is a pandemic respiratory disease caused by the SARS−CoV−2 coronavirus. The worldwide epidemiologic data showed higher mortality in males compared to females, suggesting a hypothesis about the protective effect of estrogens against severe disease progression with the ultimate end being patient’s death. This article summarizes the current knowledge regarding the potential effect of estrogens and other modulators of estrogen receptors on COVID−19. While estrogen receptor activation shows complex effects on the patient’s organism, such as an influence on the cardiovascular/pulmonary/immune system which includes lower production of cytokines responsible for the cytokine storm, the receptor-independent effects directly inhibits viral replication. Furthermore, it inhibits the interaction of IL−6 with its receptor complex. Interestingly, in addition to natural hormones, phytestrogens and even synthetic molecules are able to interact with the estrogen receptor and exhibit some anti-COVID−19 activity. From this point of view, estrogen receptor modulators have the potential to be included in the anti-COVID−19 therapeutic arsenal.

show abstract

Repurposing existing drugs: identification of SARS-CoV-2 3C-like protease inhibitors

Cited by 33 publications

References 46 publications

Antiviral Properties of the NSAID Drug Naproxen Targeting the Nucleoprotein of SARS-CoV-2 Coronavirus

Antiviral Properties of the NSAID Drug Naproxen Targeting the Nucleoprotein of SARS-CoV-2 Coronavirus

Combining Different Docking Engines and Consensus Strategies to Design and Validate Optimized Virtual Screening Protocols for the SARS-CoV-2 3CL Protease

Estrogen Receptor Modulators in Viral Infections Such as SARS−CoV−2: Therapeutic Consequences

Contact Info

Product

Resources

About