Developing New Treatments for COVID-19 through Dual-Action Antiviral/Anti-Inflammatory Small Molecules and Physiologically Based Pharmacokinetic Modeling

Broad-spectrum antiviral agents that are effective against many viruses are difficult to develop, as the key molecules, as well as the biochemical pathways by which they cause infection, differ largely from one virus to another. This was more strongly highlighted by the COVID-19 pandemic, which found health systems all over the world largely unprepared and proved that the existing armamentarium of antiviral agents is not sufficient to address viral threats with pandemic potential. The clinical protocols for the treatment of COVID-19 are currently based on the use of inhibitors of the inflammatory cascade (dexamethasone, baricitinib), or inhibitors of the cytopathic effect of the virus (monoclonal antibodies, molnupiravir or nirmatrelvir/ritonavir), using different agents. There is a critical need for an expanded armamentarium of orally bioavailable small-molecular medicinal agents, including those that possess dual antiviral and anti-inflammatory (AAI) activity that would be readily available for the early treatment of mild to moderate COVID-19 in high-risk patients. A multidisciplinary approach that involves the use of in silico screening tools to identify potential drug targets of an emerging pathogen, as well as in vitro and in vivo models for the determination of a candidate drug's efficacy and safety, are necessary for the rapid and successful development of antiviral agents with potentially dual AAI activity. Characterization of candidate AAI molecules with physiologically based pharmacokinetics (PBPK) modeling would provide critical data for the accurate dosing of new therapeutic agents against COVID-19. This review analyzes the dual mechanisms of AAI agents with potential anti-SARS-CoV-2 activity and discusses the principles of PBPK modeling as a conceptual guide to develop new pharmacological modalities for the treatment of COVID-19.

Automated summary

The development of broad-spectrum antiviral agents is difficult, as the key molecules and pathways differ greatly between viruses. The COVID-19 pandemic has highlighted the limited effectiveness of current antiviral agents. Clinical protocols for COVID-19 treatment currently focus on inhibiting inflammation or the cytopathic effect of the virus. There is a need for expanded oral antiviral agents with dual antiviral and anti-inflammatory activity for early treatment of COVID-19 in high-risk patients.