Sofosbuvir protects human brain organoids against SARS-CoV-2

Mesci, Pinar; Macia, Ángela; Saleh, Aurian; Martin-Sancho, Laura; Yin, Xin; Snethlage, Cedric E; Avansini, Simoni Helena; Chanda, Sumit K.; Muotri, Alysson R.

doi:10.1101/2020.05.30.125856

Cited by 64 publications

(89 citation statements)

References 25 publications

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“…4 Mesci et al showed that Sofosbuvir could protect human brain organoids from SARS-CoV-2 infection. 5 Considering its low toxicity, its ability to be rapidly activated to the triphosphate form by cellular enzymes, and the high intracellular stability of this active molecule, Sayad et al initiated a COVID-19 treatment clinical trial with Sofosbuvir and Velpatasvir, which together form the combination HCV drug EPCLUSA. 6 Izzi et al also advocated the use of Sofosbuvir and Velpatasvir for the treatment of COVID-19.…”

Section: Resultsmentioning

confidence: 99%

“…21 By comparing the RNA genomes of HCV and SARS-CoV-2, Buonaguro et al suggested that Sofosbuvir might be an optimal nucleotide analogue to repurpose for COVID-19 treatment. 22 Other investigators have since demonstrated the ability of Sofosbuvir to inhibit SARS-CoV-2 replication in lung and brain cells, 4,5 and COVID-19 clinical trials with EPCLUSA 6 and with Sofosbuvir plus Daclatasvir 7 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.…”

Section: Introductionmentioning

confidence: 99%

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Sofosbuvir Terminated RNA is More Resistant to SARS-CoV-2 Proofreader than RNA Terminated by Remdesivir

Jockusch

Tao

et al. 2020

Preprint

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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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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Sofosbuvir Terminated RNA is More Resistant to SARS-CoV-2 Proofreader than RNA Terminated by Remdesivir

Jockusch

Tao

et al. 2020

Preprint

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“…Similar to Ramani et al, Mesci et al ( 141 ) used these brain organoids and observed that the virus was able to infect neurons, including NPCs and mature cortical neurons, and cause cell death accompanied by the impairment of excitatory synapses. Furthermore, this work tested the efficiency of Sofosbuvir, an FDA-approved brain-penetrant antiviral drug for positive-sense single-stranded RNA viruses ( 145 ), as a treatment for the SARS-CoV-2 infection and observed that this drug was able to rescue the altered synaptogenesis and decrease neuronal death and viral accumulation in these brain organoids ( 141 ). Song et al ( 117 ) also demonstrated that SARS-CoV-2 has neuroinvasive capacity in human brain organoids, particularly of NPCs and mature cortical neurons.…”

Section: Brain Organoids As a Model Of Cns Infection By Sars-cov-2mentioning

confidence: 91%

“…To date, SARS-CoV-2 infection has been studied in human organoids of lung, liver, intestine, blood vessels, and kidney ( 42 , 118 , 136 – 138 ). Human brain organoids have also been used; these present strong cellular and structural similarities to some mammalian brain regions, such as a neural epithelium containing NPCs, that align to form a ventricular zone-like layer, cortical neurons, that contribute to the formation of a cortical plate-like layer and glial cells, such as astrocytes or oligodendrocytes ( 139 – 141 ). These organoids are useful for the study of early stages of human neurodevelopment and network formation, key cellular processes such as proliferation, differentiation, apoptosis, synaptogenesis or myelination, CNS function such as electrophysiological activity, neurodegenerative diseases, potential treatments, and have been already used for the study of other virus such as ZIKA virus or HIV ( 139 , 141 – 144 ).…”

Section: Brain Organoids As a Model Of Cns Infection By Sars-cov-2mentioning

confidence: 99%

Experimental Models for the Study of Central Nervous System Infection by SARS-CoV-2

et al. 2020

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Introduction The response to the SARS-CoV-2 coronavirus epidemic requires increased research efforts to expand our knowledge of the disease. Questions related to infection rates and mechanisms, the possibility of reinfection, and potential therapeutic approaches require us not only to use the experimental models previously employed for the SARS-CoV and MERS-CoV coronaviruses but also to generate new models to respond to urgent questions. Development We reviewed the different experimental models used in the study of central nervous system (CNS) involvement in COVID-19 both in different cell lines that have enabled identification of the virus’ action mechanisms and in animal models (mice, rats, hamsters, ferrets, and primates) inoculated with the virus. Specifically, we reviewed models used to assess the presence and effects of SARS-CoV-2 on the CNS, including neural cell lines, animal models such as mouse hepatitis virus CoV (especially the 59 strain), and the use of brain organoids. Conclusion Given the clear need to increase our understanding of SARS-CoV-2, as well as its potential effects on the CNS, we must endeavor to obtain new information with cellular or animal models, with an appropriate resemblance between models and human patients.

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“…Using enzymatic assays, sofosbuvir was shown to act as a competitive inhibitor and a chain terminator for SARS-CoV-2 RNA polymerase[22,23]. In human brain organoids, SFV protected neural cells from SARS-CoV-2-induced cell death [24].…”

Section: Introductionmentioning

confidence: 99%

The in vitro antiviral activity of the anti-hepatitis C virus (HCV) drugs daclatasvir and sofosbuvir against SARS-CoV-2

Sacramento

Fintelman-Rodrigues

Temerozo

et al. 2020

Preprint

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The infection by the Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes major public health concern and economic burden. Although clinically approved drugs have been repurposed to treat individuals with 2019 Coronavirus disease (COVID-19), the lack of safety studies and limited efficiency as well jeopardize clinical benefits. Daclatasvir and sofosbuvir (SFV) are clinically approved direct-acting antivirals (DAA) against hepatitis C virus (HCV), with satisfactory safety profile. In the HCV replicative cycle, daclatasvir and SFV target the viral enzymes NS5A and NS5B, respectively. NS5A is endowed with pleotropic activities, which overlap with several proteins from SARS-CoV-2. HCV NS5B and SARS-CoV-2 nsp12 are RNA polymerases that share homology in the nucleotide uptake channel. These characteristics of the HCV and SARS-CoV-2 motivated us to further study the activity of daclatasvir and SFV against the new coronavirus. Daclatasvir consistently inhibited the production of infectious SARS-CoV-2 virus particles in Vero cells, in the hepatoma cell line HuH-7 and in type II pneumocytes (Calu-3), with potencies of 0.8, 0.6 and 1.1 μM, respectively. Daclatasvir targeted early events during SARS-CoV-2 replication cycle and prevented the induction of IL-6 and TNF-α, inflammatory mediators associated with the cytokine storm typical of SARS-CoV-2 infection. Sofosbuvir, although inactive in Vero cells, displayed EC50 values of 6.2 and 9.5 μM in HuH-7 and Calu-3 cells, respectively. Our data point to additional antiviral candidates, in especial daclatasvir, among drugs overlooked for COVID-19, that could immediately enter clinical trials.

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Sofosbuvir protects human brain organoids against SARS-CoV-2

Cited by 64 publications

References 25 publications

Sofosbuvir Terminated RNA is More Resistant to SARS-CoV-2 Proofreader than RNA Terminated by Remdesivir

Sofosbuvir Terminated RNA is More Resistant to SARS-CoV-2 Proofreader than RNA Terminated by Remdesivir

Experimental Models for the Study of Central Nervous System Infection by SARS-CoV-2

The in vitro antiviral activity of the anti-hepatitis C virus (HCV) drugs daclatasvir and sofosbuvir against SARS-CoV-2

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