Why Certain Repurposed Drugs Are Unlikely to Be Effective Antivirals to Treat SARS-CoV-2 Infections

Viruses. 2024 Apr 22;16(4):651. doi: 10.3390/v16040651.

Abstract

Most repurposed drugs have proved ineffective for treating COVID-19. We evaluated median effective and toxic concentrations (EC50, CC50) of 49 drugs, mostly from previous clinical trials, in Vero cells. Ratios of reported unbound peak plasma concentrations, (Cmax)/EC50, were used to predict the potential in vivo efficacy. The 20 drugs with the highest ratios were retested in human Calu-3 and Caco-2 cells, and their CC50 was determined in an expanded panel of cell lines. Many of the 20 drugs with the highest ratios were inactive in human Calu-3 and Caco-2 cells. Antivirals effective in controlled clinical trials had unbound Cmax/EC50 ≥ 6.8 in Calu-3 or Caco-2 cells. EC50 of nucleoside analogs were cell dependent. This approach and earlier availability of more relevant cultures could have reduced the number of unwarranted clinical trials.

Keywords: COVID-19; SARS-CoV-2; antiviral agents; coronavirus; drug repurposing; pharmacokinetics; potency; potential efficacy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents* / pharmacology
  • Antiviral Agents* / therapeutic use
  • COVID-19 / virology
  • COVID-19 Drug Treatment*
  • Caco-2 Cells
  • Chlorocebus aethiops
  • Drug Repositioning*
  • Humans
  • SARS-CoV-2* / drug effects
  • Vero Cells

Substances

  • Antiviral Agents

Grants and funding

This research was funded in part by NIH grants 1RO1-AI-161570 NIH/NIAID (Kovari/Fitzpatrick/Schinazi), and RO1-MH-116695 NIH/NIAID (Schinazi/Tyor). We also thank the Woodruff Health Sciences 2020 COVID-19 CURE award (Tirouvanziam/Schinazi/Sukhatme), Imagine, Innovate, and Impact (I3) Team Award Emory University School of Medicine, and the Center for AIDS Research grant P30-AI-050409 NIH/NIAID (Emory University).