Potential compounds targeting the major protease of SARS-COV-2 (in vivo)

The 2019 coronavirus disease pandemic (COVID-19) is caused by a single-stranded RNA virus, namely Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). This new coronavirus appeared in the city of Wuhan, China, at the end of December 2019.

Globally, the virus is responsible for more than 188 million infections and more than 4 million deaths. As a result, health officials around the world have implemented various strategies to reduce the risk of viral spread, such as social distancing, self-isolation, face masks, etc.

Researchers have developed vaccines at a record pace and vaccination programs are underway in many countries. However, it will take a long time to vaccinate the entire world population.

Thus, there is an urgent need to develop potential therapies against COVID-19 to reduce the death rate of patients infected with COVID-19 and to treat them.

Background

SARS-CoV-2 belongs to the beta-coronavirus genus. Other members of the same genera are Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Middle East Respiratory Syndrome Coronavirus (MERS-CoV). In SARS-CoV, the main protease, namely 3CLpro, also known as Mpro, is a homodimer with three structural domains, domains I, II and III.

This protease sequence is highly conserved among SARS-CoV and MERS-CoV, showing 40-44% sequence similarity. However, researchers found more than 95% sequence homology (3CLpro protease) between SARS-CoV-2 and SARS-CoV.

By comparing genomic sequences and active sites, the two viruses showed 79% similarity. The main function of 3CLpro is to play a vital role in the replication and transcription of viral RNA. This makes 3CLpro an important anti-coronavirus target.

There is a massive demand for the identification of an effective antiviral agent with minimal side effects for the treatment of SARS-CoV-2 infection.

Now new research published in the journal Hippocracy focuses on assisting ongoing COVID-19 therapeutic research by developing a new method to identify active compounds that have the potential to fight COVID-19 infection.

For the identification of those compounds that can effectively target the SARS-CoV virus, the authors of this study combined a systematic review, meta-analyzes and molecular docking studies of some preclinical studies (in vivo) compounds.

The study

The current search conducted a systematic search for articles available in PubMed, Web of Science, and Scopus. The main strategy behind the article search was based on the methodological framework, namely, Preferred Report Items for Systematic Review and Meta-Analysis (PRISMA).

Subsequently, the researchers of this study developed a combined model based on a systematic review, meta-analyzes and molecular docking studies. The model would help assess the effect size of preclinical studies of compounds (in vivo) that have been examined against SARS-CoV.

Molecular docking analysis was performed to explore the binding model of the SARS-CoV inhibitor in the active sites of the COVID-19 protease.

The authors of the present study obtained the X-ray crystal structure of 3CLpro from SARS-CoV-2 from the RCSB protein database. Ligand and receptor complexes were prepared for the docking study using Autodock vina. The three-dimensional structure of all study compounds was constructed and structural optimization was performed.

These results were further validated by re-docking the native ligand from the crystal structures of the protein into the binding site. The authors used Accelrys’ Discovery Studio Visualizer software to study the protein-ligand complex.

After performing the systematic article search, six relevant articles were obtained that could be used for a meta-analysis. As the heterogeneity was expected to be high, the researchers in this study performed random-effect model meta-analyzes to calculate the overall prevalence of the pooled disease.

The authors of this study reported that the overall pooled random prevalence of infected mice that were treated with the selected compounds was 78.1%. However, prophylactic approaches were found to have a significantly higher overall prevalence than therapeutic approaches.

The researchers indicate that most of the SARS-CoV inhibitors analyzed so far have shown minimal efficacy in lowering the titer of the lung virus of SARS-CoV infection, studied using animal models.

Molecular docking studies have identified compounds that have the potential to inhibit the SARS-CoV-2 virus and, thus, could act as effective agents for the treatment of COVID-19 disease.

Conclusion

This study accurately summarized the evidence associated with drug development, efficacy and safety of healthcare interventions. In addition, it highlighted the methodological limitations of the studies identified through the systematic search. These limitations are mainly due to insufficient data from experimental models as well as outcome measures.

The authors revealed that ribavirin was the most studied compound. However, it was found to be less active than EIDD-2801, GS-5734, and amodiaquine. Therefore, these three compounds, namely EIDD-2801, GS-5734 and amodiaquine, could be further studied to determine their efficacy for the treatment of SARS-CoV-2 infection.