The potential of sofosbuvir against neurological symptoms of COVID-19

On March 11, 2020, the World Health Organization (WHO) announced the global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as coronavirus disease 2019 (COVID-19).

Despite the discovery of effective COVID-19 vaccines and the subsequent initiation of immunization programs worldwide, SARS-CoV-2 infections have been widely reported due to the emergence of new variants that can evade immune responses induced by both vaccination and natural infection. There is therefore still a considerable need for novel, rapidly deployable and efficient antiviral therapies.

To learn: SARS-CoV-2 infects human brain organoids, causing cell death and loss of synapses that can be rescued by treatment with sofosbuvir. Photo credit: Gorodenkoff / Shutterstock.com

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In addition to shortness of breath, COVID-19 patients also suffer from direct or indirect negative effects on the central nervous system (CNS). Several neurological symptoms such as stroke, epilepsy, anosmia, ageusia, hallucinations and encephalopathy have been associated with SARS-CoV-2 infection.

A mouse model showed that the SARS-CoV-2 spike S1 protein can cross the blood-brain barrier, suggesting that the virus can infect the brain and cause neurological symptoms. Autopsy reports from patients who died from COVID-19 showed the presence of SARS-CoV-2 in cortical neurons. In addition, the possibility of vertical transmission of SARS-CoV-2 to the fetus has been identified, which can affect the development of the fetal brain.

Human brain organoids are three-dimensional models of the brain that mimic cellular and molecular aspects of human embryonic and fetal developmental stages. Previous studies showed that human brain cortical functional organoids can accurately recapitulate the early stages of neural development and organize cortical networks.

About the study

In a recent PLoS biology Study, researchers discuss how SARS-CoV-2 infects cortical neurons and damages their synapses, which form the connection between brain cells. This research not only assesses the risk of SARS-CoV-2 infection in human brain cells, but also analyzes its impact on human brain development.

The TISSUES database helped identify proteins associated with SARS-CoV-2 infection in the human brain. Some of the proteins expressed in the brain include transmembrane serine protease 2 (TMPRSS2), angiotensin converting enzyme 2 (ACE2), neuropilin-1 (NRP1), and CD147 but not CD26.

These entry factor proteins are expressed at reduced levels in the CNS compared to other organs. For example, ACE2 and TMPRSS2 are less expressed than NRP1, which is highly expressed in the cerebral cortex and hippocampus. However, the BSG/CD147 gene is highly expressed in all brain regions.

To test whether SARS-CoV-2 could infect the developing human brain, researchers prepared eight-week-old human brain cortical organoids (BCO) using dermal fibroblasts from healthy donors. Organoids were infected with SARS-CoV-2 to determine if BCOs are susceptible to SARS-CoV-2 infection.

One of the important aspects of this research was to identify US Food and Drug Administration (FDA)-approved antiviral drugs that can alleviate neurological symptoms caused by SARS-CoV-2 infection. In this study, BCO infected with influenza A virus was used as a control using the same experimental design.

study results

Sofosbuvir (SOF) is an antiviral drug approved by the FDA for the treatment of hepatitis C (HCV). In particular, this drug can also inhibit other single-stranded viruses, including coronaviruses. As a result, the current study evaluated the effectiveness of SOF in alleviating neurological manifestations in COVID-19 patients.

Mechanistically, SOF inhibits HCV replication by restricting the activity of ribonucleic acid (RNA)-dependent RNA polymerase (RdRp). A high degree of sequence and structural similarity was found between the RdRp of SARS-CoV-2 and HCV.

Importantly, SOF-binding residues are conserved across several coronaviruses, including SARS-CoV-2. Taking these observations into account, the authors hypothesized that SOF could effectively inhibit SARS-CoV-2 replication.

A different range of SOF dosages has been used for BOC treatment. To this end, an increased SOF dose was found to be effective in lowering intracellular SARS-CoV-2 RNA levels.

Nevertheless, the strongest inhibition of SARS-CoV-2 replication without inducing cell death occurred at a SOF concentration of 20 μM. In addition, the effectiveness of SOF was validated by analyzing intracellular viral RNA and the number of viable viruses in the supernatants of SOF-treated SARS-CoV-2-infected BCOs.

Importantly, a lower number of infectious viruses was detected after antiviral treatment. Immunoblot and immunostaining experiments further validated the results mentioned above.

Therefore, experimental results underlined the effectiveness of SOF in the fight against COVID-19. Remarkably, SOF treatment not only reduced SARS-CoV-2 virus protein levels, but also decreased virus-induced cell death.

Nestin+ NPCs and MAP2+ neurons have been found to be susceptible to SARS-CoV-2 infection. Elevated levels of the SARS-CoV-2 nucleocapsid protein in BCO were associated with increased cell death in both neurons and neural progenitor (NPC) cells.

To assess the impact of COVID-19 on synaptic integrity, the number of excitatory synapses in neurons was quantified using Synapsin 1, vGLUT1, and PSD95 antibodies. A significant decrease in presynaptic proteins was observed during SARS-CoV-2 infection, which could be effectively alleviated by SOF treatment.

Conclusions

Although experimental results demonstrated the effectiveness of SOF in improving neurological conditions in COVID-19 patients, further clinical evaluations are needed for further validation. Nevertheless, SOF seems to be a promising drug to prevent the development of neurological symptoms in COVID-19 patients.

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