The coronavirus disease 2019 (COVID-19) disease pandemic is caused by a single-stranded RNA virus, namely, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This novel coronavirus emerged in Wuhan City, China, in late December 2019.
Globally, the virus is responsible for over 188 million infections and more than 4 million deaths. As a result, health officials worldwide implemented various strategies to reduce the risk of viral spread, such as social distancing, self-isolation, facemasks, etc.
Researchers developed vaccines at a record pace, and vaccination programs are underway in many countries. However, a substantial amount of time will be needed to vaccinate the entire world's population.
Thus, the need to develop potential COVID-19 therapeutics to reduce the mortality rate of patients with COVID-19 infection and treat them is urgent.
Background
SARS-CoV-2 belongs to the genera betacoronavirus. 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, which is also known as Mpro, is a homodimer with three structural domains, domain I, II, and III.
This protease sequence is highly conserved among SARS-CoV and MERS-CoV, exhibiting 40-44% sequence similarity. However, researchers have found more than 95% of sequence homology (3CLpro protease) between SARS-CoV-2 and SARS-CoV.
While comparing the genomic sequences and active sites, both the viruses showed 79% similarity. The primary function of 3CLpro is that it plays 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 Hippokratia focuses on assisting the ongoing COVID-19 therapeutic research by developing a new method to identify active compounds that have the potential to fight against COVID-19 infection.
For the identification of such compounds that can effectively target the SARS-CoV virus, the authors of this study have combined systematic review, meta-analyses, and molecular docking studies of selected preclinical (in vivo) compounds.
The study
The current research has conducted a systematic search of articles available in PubMed, Web of Science, and Scopus. The primary strategy behind searching articles was based on the methodological framework, namely, Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA).
Subsequently, researchers of this study have developed a combined model that is based on a systematic review, meta-analyses, and molecular docking studies. The model would help evaluate the effect size of preclinical studies of compounds (in vivo) that have been examined against SARS-CoV.
The molecular docking analysis was carried out to explore the SARS-CoV inhibitor's binding pattern in the active sites of the COVID-19 protease.
The authors of the current study obtained the X-ray crystal structure of SARS-CoV-2's 3CLpro from the RCSB Protein Data Bank. The ligand and receptor complexes were prepared for the docking study using Autodock vina. The three-dimensional structure of all the study compounds was constructed, and structural optimization was carried out.
These results were further validated by redocking the native ligand of the protein crystal structures into the binding site. The authors used Accelrys's Discovery Studio Visualizer software for studying the protein-ligand complex.
After conducting the systematic search for articles, six relevant articles were obtained which could be used for meta-analysis. As heterogeneity was expected to be high, researchers of this study performed a random effect model meta-analyses to calculate the overall pooled disease prevalence.
The authors of this study have reported that the overall random pooled prevalence of infected mice that were treated with the selected compounds was 78.1%. However, prophylactic approaches were found to have a significantly higher pooled prevalence compared to therapeutics.
The researchers indicate that most of the SARS-CoV inhibitors analyzed so far have shown minimal effectivity in lowering the lung virus titer of SARS-CoV infection, studied using animal models.
The molecular docking studies have identified compounds that have the potential to inhibit the SARS-CoV-2 virus and, thereby, could act as effective agents for the treatment of COVID-19 disease.
Conclusions
This study has precisely summarized evidence associated with drug development, efficacy, and healthcare interventions safety. Additionally, it has highlighted the methodological limitations of the studies identified via systematic search. These limitations mainly arose due to insufficient data from the experimental designs as well as the 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, i.e., EIDD-2801, GS-5734, and amodiaquine, could be further studied to determine their efficacy for the treatment of SARS-CoV-2 infection.
Vaping increases susceptibility to COVID-19 infection, study finds