The Potential of Sofosbuvir for Neurological Symptoms of COVID-19

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

Despite the discovery of an effective COVID-19 vaccine and the subsequent initiation of vaccination programs around the world, SARS-CoV-2 infection still escapes immune responses induced by both vaccination and natural infection. It has been widely reported due to the emergence of new mutants capable of Therefore, there remains a significant need for novel, rapidly deployable and efficient antiviral therapies.

study: SARS-CoV-2 infects human brain organoids, causing cell death and synaptic loss that can be rescued by treatment with sofosbuvir. Image credit: Gorodenkoff / Shutterstock.com

Background

In addition to respiratory distress, COVID-19 patients directly or indirectly affect the central nervous system (CNS). Several neurological conditions such as stroke, epilepsy, dysosmia, aging, hallucinations and encephalopathy are associated with SARS-CoV-2 infection.

A mouse model has shown that the SARS-CoV-2 spike S1 protein can cross the blood-brain barrier, allowing the virus to infect the brain and induce neurological symptoms. An autopsy report of a patient who died of COVID-19 showed the presence of her SARS-CoV-2 in cortical neurons. In addition, potential vertical transmission of SARS-CoV-2 to the fetus has been discovered, which may affect fetal brain development.

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 have revealed that human cortical functional organoids can closely recapitulate early stages of neurodevelopment and organize cortical networks.

About research

recently PLoSbiology Researchers discuss how SARS-CoV-2 infects cortical neurons and damages synapses that form connections between brain cells. This study not only assesses the risk of SARS-CoV-2 infection in human brain cells, but also analyzes the effects on the developing human brain.

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 the transmembrane serine protease 2 (TMPRSS2), angiotensin-converting enzyme 2 (ACE2), neuropilin-1 (NRP1), and CD147, but not CD26.

These invasion factor proteins have reduced expression levels in the CNS compared to other organs. For example, ACE2 and TMPRSS2 are under-expressed compared to 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 infects the developing human brain, researchers used dermal fibroblasts from healthy donors to grow 8-week-old human brain cortical organoids ( BCO) was created. To determine whether BCO is vulnerable to SARS-CoV-2 infection, we infected organoids with SARS-CoV-2.

One of the key aspects of this research was to identify U.S. Food and Drug Administration (FDA)-approved antiviral drugs that can alleviate neurological symptoms caused by SARS-CoV-2 infection. In this study, using the same design, BCOs infected with influenza A virus were used as controls.

Survey results

Sofosbuvir (SOF) is an FDA-approved antiviral drug for the treatment of hepatitis C (HCV). In particular, the drug can also inhibit other single-stranded viruses such as: coronavirusAs a result, the current study assessed efficacy of SOF in alleviation of neurological symptoms in COVID-19 patients.

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

Importantly, SOF-binding residues are conserved among several coronaviruses, including SARS-CoV-2. Considering these observations, the authors hypothesized that his SOF could effectively inhibit SARS-CoV-2 replication.

Various ranges of SOF dosages were used for BOC treatment. To this end, we found that increasing doses of SOF effectively decreased intracellular SARS-CoV-2 RNA levels.

Nevertheless, the highest inhibition of SARS-CoV-2 replication, without inducing cell death, occurred at a SOF concentration of 20 μM. Furthermore, the efficacy of SOF was validated by analyzing intracellular viral RNA and viable virus numbers present in the supernatant of SOF-treated SARS-CoV-2-infected BCOs.

Importantly, the number of infectious viruses detected after antiviral treatment decreased. Immunoblotting and immunostaining experiments further validated the aforementioned findings.

Therefore, the results emphasized the effectiveness of SOF in fighting COVID-19. Notably, SOF treatment not only reduced the protein levels of the SARS-CoV-2 virus, but also decreased virus-induced cell death.

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

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

Conclusion

Experimental results have demonstrated the efficacy of SOF in improving the neurological status of COVID-19 patients, but more clinical evaluations are needed for further validation. Nonetheless, SOF appears to be a promising drug for preventing the development of neurological symptoms in his COVID-19 patients.