Sofosbuvir and daclatasvir compared with standard of care in the treatment of patients admitted to hospital with moderate or severe coronavirus infection (COVID-19): a randomized controlled trial

Sadeghi, Anahita; Asgari, Ali; Norouzi, Alireza; Kheiri, Zahedin; Anushirvani, Amir; Montazeri, Mahnaz; Hosamirudsai, Hadiseh; Afhami, Shirin; Akbarpour, Elham; Aliannejad, Rasoul; Radmard, Amir Reza; Davarpanah, Amir H.; Levi, Jacob; Wentzel, Hannah; Qavi, Ambar; Garratt, Anna; Simmons, Bryony; Hill, Andrew; Merat, Shahin

doi:10.1093/jac/dkaa334

Cited by 107 publications

(125 citation statements)

References 31 publications

(24 reference statements)

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“…46 The structures of the SARS-CoV-2 RNA-dependent RNA polymerase nsp12 and its complex with nsp7 and nsp8 have been determined by cryo-EM, 49,50 Daclatasvir (DCV) to treat moderate or severe COVID-19 patients. 59 These investigators showed that SOF/DCV treatment increased 14-day clinical recovery rates and reduced hospital stays. Two similar SOF/DCV clinical trials were also performed and provided evidence that this drug combination may have some benefit; 60,61 the authors recommended that larger well-controlled randomized trials are necessary to confirm their results.…”

Section: F I G U R E 4 Incorporation Of 2'-fme-utp 3'-f-dttp and 3'mentioning

confidence: 99%

Nucleotide analogues as inhibitors of SARS‐CoV Polymerase

Kumar

et al. 2020

Pharmacology Res & Perspec

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SARS‐CoV‐2, a member of the coronavirus family, has caused a global public health emergency. Based on our analysis of hepatitis C virus and coronavirus replication, and the molecular structures and activities of viral inhibitors, we previously reasoned that the FDA‐approved hepatitis C drug EPCLUSA (Sofosbuvir/Velpatasvir) should inhibit coronaviruses, including SARS‐CoV‐2. Here, using model polymerase extension experiments, we demonstrate that the active triphosphate form of Sofosbuvir is incorporated by low‐fidelity polymerases and SARS‐CoV RNA‐dependent RNA polymerase (RdRp), and blocks further incorporation by these polymerases; the active triphosphate form of Sofosbuvir is not incorporated by a host‐like high‐fidelity DNA polymerase. Using the same molecular insight, we selected 3’‐fluoro‐3’‐deoxythymidine triphosphate and 3’‐azido‐3’‐deoxythymidine triphosphate, which are the active forms of two other anti‐viral agents, Alovudine and AZT (an FDA‐approved HIV/AIDS drug) for evaluation as inhibitors of SARS‐CoV RdRp. We demonstrate the ability of two of these HIV reverse transcriptase inhibitors to be incorporated by SARS‐CoV RdRp where they also terminate further polymerase extension. Given the 98% amino acid similarity of the SARS‐CoV and SARS‐CoV‐2 RdRps, we expect these nucleotide analogues would also inhibit the SARS‐CoV‐2 polymerase. These results offer guidance to further modify these nucleotide analogues to generate more potent broad‐spectrum anti‐coronavirus agents.

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Section: F I G U R E 4 Incorporation Of 2'-fme-utp 3'-f-dttp and 3'mentioning

confidence: 99%

Nucleotide analogues as inhibitors of SARS‐CoV Polymerase

Kumar

et al. 2020

Pharmacology Res & Perspec

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“…Other investigators have since demonstrated the ability of Sofosbuvir to inhibit SARS-CoV-2 replication in lung and brain cells 18,19 , and COVID-19 clinical trials with EPCLUSA 20 and with Sofosbuvir plus Daclatasvir 21 have been initiated in several countries. Recently, Sadeghi et al reported encouraging results from a clinical trial using Sofosbuvir (SOF) and Daclatasvir (DCV) as a potential combination treatment for moderate or severe COVID-19 patients 22 . In a study involving 66 patients, these investigators showed that SOF/ DCV treatment increased 14-day clinical recovery rates and reduced the length of hospital stays.…”

mentioning

confidence: 99%

Sofosbuvir terminated RNA is more resistant to SARS-CoV-2 proofreader than RNA terminated by Remdesivir

Jockusch

Tao

et al. 2020

Sci Rep

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SARS-CoV-2 is responsible for COVID-19, resulting in the largest pandemic in over a hundred years. After examining the molecular structures and activities of hepatitis C viral inhibitors and comparing hepatitis C virus and coronavirus replication, we previously postulated that the FDA-approved hepatitis C drug EPCLUSA (Sofosbuvir/Velpatasvir) might inhibit SARS-CoV-2. We subsequently demonstrated that Sofosbuvir triphosphate is incorporated by the relatively low fidelity SARS-CoV and SARS-CoV-2 RNA-dependent RNA polymerases (RdRps), serving as an immediate polymerase reaction terminator, but not by a host-like high fidelity DNA polymerase. Other investigators have since demonstrated the ability of Sofosbuvir to inhibit SARS-CoV-2 replication in lung and brain cells; additionally, COVID-19 clinical trials with EPCLUSA and with Sofosbuvir plus Daclatasvir have been initiated in several countries. SARS-CoV-2 has an exonuclease-based proofreader to maintain the viral genome integrity. Any effective antiviral targeting the SARS-CoV-2 RdRp must display a certain level of resistance to this proofreading activity. We report here that Sofosbuvir terminated RNA resists removal by the exonuclease to a substantially higher extent than RNA terminated by Remdesivir, another drug being used as a COVID-19 therapeutic. These results offer a molecular basis supporting the current use of Sofosbuvir in combination with other drugs in COVID-19 clinical trials.

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“…Subgenomic mRNAs are produced by discontinuous transcrip-tion, a process characteristic of this RdRp, which favors recombination. Compounds such as remdesivir, favipiravir, and sofosbuvir block this enzyme [39][40][41]45]. The subgenomic mRNAs are then translated into protein.…”

Section: Targeting Viral Enzymesmentioning

confidence: 99%

“…Remdesivir similarly to sofosbuvir, a direct-acting antiviral used in HCV therapy, is a chain-terminating nucleotide analog. These drugs produce their therapeutic effect by directly interacting with the RdRp and incorporating the active form of the inhibitor into the growing RNA strand, preventing the replication to continue [40,41]. Several clinical trials have been conducted evaluating the activity of remdesivir and other direct-acting antivirals used in HCV against SARS-CoV-2 [42].…”

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confidence: 99%

Understanding Severe Acute Respiratory Syndrome Coronavirus 2 Replication to Design Efficient Drug Combination Therapies

et al. 2020

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Background: The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its disease COVID-19 has strongly encouraged the search for antiviral compounds. Most of the evaluated drugs against SARS-CoV-2 derive from drug repurposing of Food and Drug Administration-approved molecules. These drugs have as target three major processes: (1) early stages of virus-cell interaction, (2) viral proteases, and (3) the viral RNA-dependent RNA polymerase. Summary: This review focused on the basic principles of virology and pharmacology to understand the importance of early stages of virus-cell interaction as therapeutic targets and other main processes vital for SARS-CoV-2 replication. Furthermore, we focused on describing the main targets associated with SARS-CoV-2 antiviral therapy and the rationale of drug combinations for efficiently suppressing viral replication. Key Messages: We hypothesized that blocking of both entry mechanisms could allow a more effective antiviral effect compared to the partial results obtained with chloroquine or its derivatives alone. This approach, already used to achieve an antiviral effect higher than that offered by every single drug administered separately, has been successfully applied in several viral infections such as HIV and HCV. This review will contribute to expanding the perception of the possible therapeutic targets in SARS-CoV-2 infection and highlight the benefits of using combination therapies.

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Sofosbuvir and daclatasvir compared with standard of care in the treatment of patients admitted to hospital with moderate or severe coronavirus infection (COVID-19): a randomized controlled trial

Cited by 107 publications

References 31 publications

Nucleotide analogues as inhibitors of SARS‐CoV Polymerase

Nucleotide analogues as inhibitors of SARS‐CoV Polymerase

Sofosbuvir terminated RNA is more resistant to SARS-CoV-2 proofreader than RNA terminated by Remdesivir

Understanding Severe Acute Respiratory Syndrome Coronavirus 2 Replication to Design Efficient Drug Combination Therapies

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