An in-depth analysis of pathogenesis of SARS-CoV-2 and therapeutic options for COVID-19

By Dr. Sanchari Sinha Dutta, Ph.D.Reviewed by Benedette Cuffari, M.Sc.Apr 3 2022

In a recent Reviews in Medical Virology article, scientists discuss the pathogenic characteristics of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and available therapeutic interventions for treating the coronavirus disease 2019 (COVID-19). Herein, the authors also review emerging technologies and interdisciplinary approaches that are playing a crucial role in COVID-19 diagnosis and antiviral drug discovery.

Study: SARS-CoV-2: Mechanism of infection and emerging technologies for future prospects. Image Credit: Blue Planet Studio / Shutterstock.com

Background

The ongoing COVID-19 pandemic continues to be a major public health crisis. SARS-CoV-2, which is the causative pathogen for COVID-19, is an enveloped, positive-sense, and single-stranded ribonucleic acid (RNA) virus. As a respiratory virus, SARS-CoV-2 primarily attacks the alveolar epithelial cells; however, SARS-CoV-2 has also been detected in other organs, including the intestines, liver, brain, heart, and kidneys.

Mechanism of viral entry and infection

The spike glycoprotein expressed on the surface of SARS-CoV-2 plays a vital role in initiating viral entry into host cells. The spike protein consists of two subunits including the S1 and S2 subunits.

Within the S1 subunit, the receptor-binding domain (RBD) binds to the host cell angiotensin-converting enzyme 2 (ACE2) receptor to initiate viral entry. The cleavage of the spike protein by host cell proteases like the transmembrane serine protease 2 (TMPRSS) leads to dissociation between S1 and S2 subunits, which then exposes the fusion peptide present in the S2 subunit. This is followed by fusion between the viral envelope and host cell membrane and the subsequent release of viral material into host cells.

Upon entry, viral RNA is translated to form polyproteins, which are subsequently cleaved by viral proteases to form a replication-transcription complex. During replication, a full-length negative-sense RNA copy of the viral genome is synthesized, which acts as a template for the generation of a full-length positive-sense RNA genome.

During transcription, subgenomic RNAs encoding structural proteins are generated. Afterward, the genomic RNA and proteins are assembled to form viral particles, which are then released from the infected cells through exocytosis.

Clinical characteristics of COVID-19

The clinical presentation of COVID-19 can range from asymptomatic or mildly symptomatic to severe pneumonia, respiratory failure, and death.

The hyperinflammatory response is one of the major hallmarks of severe COVID-19. This condition is characterized by aberrant activation of the type 1 interferon (IFN) pathway and excessive secretion of pro-inflammatory cytokines and chemokines, which are collectively known as the cytokine storm.

Additionally, a reduction in T-cells or the functional inactivation of T-cells has been observed in severe cases. Taken together, these factors result in pulmonary tissue damage and lung edema formation.  

At the systemic level, COVID-19 is characterized by reduced leukocyte and lymphocyte counts and increased C-reactive protein (CRP) levels. A reduction in CD4+ and CD8+ T-cells has also been observed in severe cases.

Treatments for COVID-19

To date, no specific antiviral medicine is available to treat COVID-19 patients. Several clinically approved antiviral medicines have been repurposed to treat critically ill COVID-19 patients, including lopinavir/ritonavir, which are inhibitors of viral main protease, and remdesivir, which inhibits the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp).

However, these medicines have generated mixed responses in both clinical trials and real-world situations. While lopinavir/ritonavir has mostly failed to show any therapeutic benefits, remdesivir has shown some promising outcomes, including faster recovery and amelioration of symptom intensity.

At the beginning of the pandemic, some studies highlighted the potential therapeutic benefits of the anti-malarial drugs chloroquine and hydroxychloroquine. However, several large-scale clinical trials failed to show any clinical benefit of these drugs.

Several small molecule inhibitors, peptides, nucleic acid oligomers, and monoclonal antibodies have also been investigated as potential therapeutic interventions against COVID-19. Monoclonal antibodies targeting the SARS-CoV-2 RBD have shown promising outcomes. In addition, convalescent plasma therapy containing anti-SARS-CoV-2 antibodies derived from COVID-19 recovered patients has shown therapeutic benefits in critically ill COVID-19 patients.

Traditional Chinese medicines have also shown high efficacy in inhibiting SARS-CoV-2 infection in vitro. To this end, some studies have shown that when these medicines are used as adjuvant therapy, they are highly potent in increasing viral clearance, reducing inflammation and tissue damage, and improving immune functions.

COVID-19 vaccines

A wide variety of COVID-19 vaccines have been developed in record time and speed. These include messenger RNA (mRNA)-based, adenoviral vector-based, inactivated virus, recombinant protein, and DNA vaccines.

In both clinical trials and real-world applications, some of these vaccines have shown high efficacy in preventing SARS-CoV-2 infection, symptomatic and severe COVID-19, hospitalization, and mortality.

Novel technologies against SARS-CoV-2

Certain emerging technologies have also been studied for their potential to assist in the development of improved diagnostics and therapeutics against SARS-CoV-2. One example is the degradation of viral proteins using PROTACs technology.

PROTACs are bifunctional molecules that consist of a viral protein-targeting ligand, an E3 ligase-targeting ligand, and a linker. This technology is associated with several advantages as compared to conventional small molecule inhibitors, such as the low requirement of reagents, as well as high specificity and accuracy.

CRISPR-based gene-editing technology is considered a promising approach to rapidly detect viral RNA, which is beneficial for the early diagnosis of COVID-19 and ongoing surveillance of novel viral variants.     

Single-nucleotide-specific programmable riboregulators (SNIPRs) technology is another novel approach for the high-precision detection of genetic mutations. SNIPR technology can be used as a cost-effective, rapid, accurate, and portable tool for identifying single-nucleotide mutations and diagnosing COVID-19.