Antiviral Drug Discovery for the Treatment of COVID-19 Infections

Abstract

The coronavirus disease 2019 (COVID-19) pandemic is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a recently emerged human coronavirus. COVID-19 vaccines have proven to be successful in protecting the vaccinated from infection, reducing the severity of disease, and deterring the transmission of infection. However, COVID-19 vaccination faces many challenges, such as the decline in vaccine-induced immunity over time, and the decrease in potency against some SARS-CoV-2 variants including the recently emerged Omicron variant, resulting in breakthrough infections. The challenges that COVID-19 vaccination is facing highlight the importance of the discovery of antivirals to serve as another means to tackle the pandemic. To date, neutralizing antibodies that block viral entry by targeting the viral spike protein make up the largest class of antivirals that has received US FDA emergency use authorization (EUA) for COVID-19 treatment. In addition to the spike protein, other key targets for the discovery of direct-acting antivirals include viral enzymes that are essential for SARS-CoV-2 replication, such as RNA-dependent RNA polymerase and proteases, as judged by US FDA approval for remdesivir, and EUA for Paxlovid (nirmatrelvir + ritonavir) for treating COVID-19 infections. This review presents an overview of the current status and future direction of antiviral drug discovery for treating SARS-CoV-2 infections, covering important antiviral targets such as the viral spike protein, non-structural protein (nsp) 3 papain-like protease, nsp5 main protease, and the nsp12/nsp7/nsp8 RNA-dependent RNA polymerase complex.

COVID-19 Rebound After Paxlovid Treatment: A Case Series and Review of Literature

“…Developing therapies have proven to be important in order to prevent severe infection especially in individuals who have a high risk of progression to severe disease. Current therapies include neutralizing antibodies targeting M spike protein and antivirals targeting vital steps in viral replication [ 2 ]. On December 22, 2021, an emergency use authorization (EUA) was issued by the United States Food and Drug Administration (FDA) for the oral main protease (M pro) inhibitor nirmatrelvir and ritonavir to be used in the treatment of patients with mild-to-moderate COVID-19 who are at a risk of progression to severe disease [ 3 ].…”

Inhibitors of Activin Receptor-like Kinase 5 Interfere with SARS-CoV-2 S-Protein Processing and Spike-Mediated Cell Fusion via Attenuation of Furin Expression

“…Drugs currently approved in the EU include monoclonal antibodies directed against the spike protein (Regkirona, Ronapreve, and Xevudy) or the interleukin-6 receptor (RoActemra), an interleukin-1 receptor antagonist (Kineret), and three drugs directly targeting the virus (Paxlovid, Veklury, and Lagevrio). The directly acting antivirals potently interfere with SARS-CoV-2 replication in cell culture; however, they are of limited effec-tiveness in advanced COVID-19 [67]. Thus, there is an additional need for novel therapy options which may include drugs that combine antiviral and immunomodulatory activities.…”

Erythromycin, Retapamulin, Pyridoxine, Folic acid and Ivermectin dose dependently inhibit cytopathic effect, Papain-like Protease and MPROof SARS-CoV-2

“…Although effect on SARS-CoV-2 induced CPE in Vero cells, SARS-CoV-2 Main protease (M PRO ) and Papain-like protease (PP) were evaluated, these were not considered necessarily linked (mechanistic) because the initial in silico selection was based on predicted activity at 11 independent targets 4 , any combination of which may be related to observed inhibition of CPE. It is interesting that Nirmatrelvir-ritonavir combination(Paxlovid) 17,18 , the current forerunner in COVID-19 therapeutics is an M PRO inhibitor and it is accepted that its efficacy is related to this inhibition 19 .…”