Cytopathic SARS-CoV-2 screening on VERO-E6 cells in a large-scale repurposing effort

Zaliani, Andrea; Vangeel, Laura; Reinshagen, Jeanette; Iaconis, Daniela; Kuzikov, Maria; Keminer, Oliver; Wolf, Markus; Ellinger, Bernhard; Esposito, Francesca; Corona, Angela; Tramontano, Enzo; Manelfi, Candida; Herzog, Katja; Jochmans, Dirk; Jonghe, Steven De; Chiu, Winston; Francken, Thibault; Schepers, Joost; Collard, C.; Abbasi, Kayvan; Claussen, Carsten; Summa, Vincenzo; Beccari, Andrea R.; Neyts, Johan; Gribbon, Philip; Leyssen, Pieter

doi:10.1038/s41597-022-01532-x

Cited by 20 publications

(20 citation statements)

References 42 publications

(48 reference statements)

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“…After data standardisation and the removal of duplicate entries (see Methods), we were left with a final dataset of 7817 compounds ( Figure 1 ). From here, the results of nine in vitro antiviral assays were mapped to the database [ 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ]. These assays are summarised in Section 2.3 .…”

Section: Resultsmentioning

confidence: 99%

“…Using an iterative approach, the CoviRx database was subjected to a series of filtering criteria to identify those with potential for repurposing against SARS-CoV-2. The first filter sought to identify compounds for which at least one in vitro assay result was present [ 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ]. The assays are summarised in Figure 3 .…”

Section: Resultsmentioning

confidence: 99%

“…All the available SARS-CoV-2 assay data of the FDA/TGA approved drugs were extracted using the drug identifiers from ChEMBL and other published datasets ( Figure 2 ) [ 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ]. The 3539 drugs with 13,919 assay datasets were ranked for activity.…”

Section: Methodsmentioning

confidence: 99%

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Systematic Down-Selection of Repurposed Drug Candidates for COVID-19

MacRaild

Mohammed

Faheem

et al. 2022

IJMS

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SARS-CoV-2 is the cause of the COVID-19 pandemic which has claimed more than 6.5 million lives worldwide, devastating the economy and overwhelming healthcare systems globally. The development of new drug molecules and vaccines has played a critical role in managing the pandemic; however, new variants of concern still pose a significant threat as the current vaccines cannot prevent all infections. This situation calls for the collaboration of biomedical scientists and healthcare workers across the world. Repurposing approved drugs is an effective way of fast-tracking new treatments for recently emerged diseases. To this end, we have assembled and curated a database consisting of 7817 compounds from the Compounds Australia Open Drug collection. We developed a set of eight filters based on indicators of efficacy and safety that were applied sequentially to down-select drugs that showed promise for drug repurposing efforts against SARS-CoV-2. Considerable effort was made to evaluate approximately 14,000 assay data points for SARS-CoV-2 FDA/TGA-approved drugs and provide an average activity score for 3539 compounds. The filtering process identified 12 FDA-approved molecules with established safety profiles that have plausible mechanisms for treating COVID-19 disease. The methodology developed in our study provides a template for prioritising drug candidates that can be repurposed for the safe, efficacious, and cost-effective treatment of COVID-19, long COVID, or any other future disease. We present our database in an easy-to-use interactive interface (CoviRx that was also developed to enable the scientific community to access to the data of over 7000 potential drugs and to implement alternative prioritisation and down-selection strategies.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Systematic Down-Selection of Repurposed Drug Candidates for COVID-19

MacRaild

Mohammed

Faheem

et al. 2022

IJMS

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“…Our assay is based on syncytia formation, which might not recapitulate accurately the fusion of the viral and cellular membranes occurring during an infection. Consequently, at this point, we decide to analyze the effect of the hit compounds on the viral growth of SARS-CoV-2 (15,18,19). Based on our previous results we decided to focus on Ethaverine, Rabeprazole, and Ethynylestradiol.…”

Section: Effect Of Ethaverine Rabeprazole and Ethynylestradiol On The...mentioning

confidence: 99%

Identification of small molecules with virus growth enhancement properties

García-Murria

Gadea-Salom

Moreno

et al. 2022

Preprint

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The novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused the pandemic disease known as coronavirus disease 2019 (COVID-19). COVID-19 vaccines were developed at record speed and were authorized approximately a year after the original outbreak. This fast response saved the lives of countless individuals and reduced the disease burden of many more. The experience has served as a reminder of the necessity to implement solid vaccine development platforms and fast production pipelines. Manufacturing vaccines for enveloped viruses, including some SARS-CoV-2 vaccines, often relies on the production of large quantities of viruses in vitro. Thus, speeding up or increasing virus production would expedite vaccine development. With this objective in mind, we established a high throughput screening (HTS) to identify small molecules that enhance or speed up host-virus membrane fusion. Among the HTS hits, we identified that ethynylestradiol augments SARS-CoV-2 fusion activity in both the absence and presence of TMPRSS2. Furthermore, we confirmed that ethynylestradiol can boost the growth of not only SARS-CoV-2 but also Influenza A virus in vitro. A small molecule with these characteristics could be implemented to improve vaccines production.

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“…More generally, the E4C project achieved outstanding results, as witnessed by some relevant deliverables: (1) overall, the E4C consortium identified about 600 new active molecules by producing more than 70,000 screening data—in this context, the results from a large-scale repurposing campaign by cytopathic SARS-CoV-2 screening of VERO-E6 cells have been recently published [ 11 ]; (2) these intensive and multifaceted computational efforts culminated in the largest and fastest virtual screening simulation ever run, in which more than 1 trillion docking simulations were run within a single shoot, along with the deployment of ad hoc virtual screening protocols and the X-ray validation of the most relevant findings [ 12 , 13 ]; (3) a new suite of open bioinformatics and simulation tools was released to the global research community—this includes three web platforms that comprise the most complete (>60 simulations) and informative (>10 µs) sets of SARS-CoV-2 molecular dynamics simulations, which were enabled by the use the best European HPC resources; (4) finally, a clinical candidate, raloxifene, which stemmed from the repurposing efforts, completed a trial to test its safety and efficacy with the enrolment of 150 patients in three EU countries, as recently reported [ 14 ].…”

mentioning

confidence: 99%