The coronavirus disease 2019 (COVID-19) pandemic has caused global health and economic crises, largely due to the rapid transmission of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and high mortality rate among high-risk groups.
Study: Therapeutically effective covalent spike protein inhibitors in treatment of SARS-CoV-2. Image Credit: Design_Cells / Shutterstock.com
Targeting the SARS-CoV-2 spike protein
The SARS-CoV-2 spike protein is largely responsible for its pathogenicity, with the receptor-binding domain (RBD) of the S1 subunit able to bind to angiotensin-converting enzyme 2 (ACE2), amongst other receptors, in order to promote viral entry.
The N-terminal of the S2 subunit is also responsible for membrane fusion. As a result, many monoclonal antibody treatments and vaccines have targeted various components of the spike protein, as it not only allows the immune system to target the virus but also prevents it from entering the cell.
While global vaccination programs are taking place, there is evidence of reduced vaccine efficacy against new SARS-CoV-2 variants. There is also limited availability of vaccines to various areas of the world that may not begin vaccination campaigns until at least 2022.
Thus, there remains a significant need for new and effective drugs that can be used to treat COVID-19.
As new drug development takes time, most current efforts are focused on drug repurposing. Some drugs have already been repurposed and approved for use against COVID-19, including chloroquine, lopinavir, arbidol, and ribavirin.
Unofficial drug repurposing has also been conducted using both approved drugs like remdesivir, as well as pseudoscientific cure-alls such as colloidal silver. These types of treatments can have dangerous side effects; thus, doctors warn against taking these medications for COVID-19.
The researchers of the current study split new drugs into two categories, including those that act on SARS-CoV-2 and those that act on the immune system of the patient. Within the category of drugs that can act on SARS-CoV-2 are several subcategories including those involved in viral ribonucleic acid (RNA) replication and synthesis inhibitors, as well as those that inhibit the binding of the virus with human cell receptors.
One of the most recent studies into potential candidates identified neratinib, [Z]-dacomitinib, trapoxin B, HKI-357, and domatinostat, which block CatB, preventing the cleavage of the spike protein that is required for viral cell entry. Additionally, [S]-boceprevir, [R]-boceprevir, aceneuramic acid, and lodoxamide have been identified, all of which inhibit TMPRSS2, another protease that can prime the spike protein through cleavage.
Camostat is a TMPRSS2 inhibitor that prevents the priming of the spike protein, thus preventing cell entry. It is approved for the use of pancreatitis and reflux in Japan and is associated with few side effects. Recent studies have has shown that this drug is potentially effective in its activity against SARS-CoV-2.
Afatinib is a small molecule tyrosine kinase inhibitor that targets epidermal growth factor receptors (EGFR). It promotes angiogenesis, cell propagation, and reduces apoptosis.
Afatinib is primarily used in cancer patients with COVID-19, as a significantly worse prognosis is seen when patients have both conditions. This is particularly true for many lung cancer patients who are treated with EGFR-TKIs, as this can lead to inflammation and pneumonia.
Emodin is an anthraquinone phytochemical that has the potential to block the interaction between the SARS-CoV-2 RBD and ACE2 receptor, thus reducing the chance of infection, as well as further transmission and spread of SARS-CoV-2 within the body. This agent is both anti-viral and anti-inflammatory, thereby suggesting that it could also lower lung damage in those already infected. Unfortunately, emodin is associated with many toxic effects; therefore, the limited available research on this drug does not justify its use at this time.
Studies identifying molecular docking, as well as in silico analyses, have identified N-[2-aminoethyl]-1 aziridine–ethanamine as a powerful ACE2 inhibitor that could prevent SARS-CoV RBD binding to the cell and ultimately inhibit viral entry. Like emodin, limited research is available on this agent and they have not been tested against COVID-19.
Ribavirin is a guanosine analog that inhibits the reproduction of ribonucleic acid (RNA) and deoxyribonucleic acid (DNA) viruses by blocking RNAP. This agent can also hinder RNA capping, thus allowing RNA degradation and the destabilization of viral RNA.
Previously, ribavirin was found to be effective during the Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-Cov outbreaks; however, there is little current information on its reliability against SARS-CoV-2. This drug can also cause anemia in some patients; therefore, current evidence suggests it does not show great effectivity against SARS-CoV-2 on its own. However, it could be used in combination therapy.
The authors highlight the potential effectiveness of these drugs, along with others that are currently being evaluated in clinical trials against COVID-19 including ritonavir, azithromycin, and chloroquine/hydroxychloroquine. As more potential tools against this disease are being discovered, the researchers hope that these efforts, alongside mass vaccination programs and monoclonal/neutralizing antibody therapies, will help to finally contain the COVID-19 pandemic.