Why Certain Repurposed Drugs Are Unlikely to Be Effective Antivirals to Treat SARS-CoV-2 Infections
Selwyn J. Hurwitz,
Ramyani De,
Julia C. LeCher,
Jessica A. Downs-Bowen,
Shu Ling Goh,
Keivan Zandi,
Tamara McBrayer,
Franck Amblard,
Dharmeshkumar Patel,
James J. Kohler,
Manoj Bhasin,
Brian S. Dobosh,
Vikas Sukhatme,
Rabindra M. Tirouvanziam,
Raymond F. Schinazi
Affiliations
Selwyn J. Hurwitz
Center for ViroScience and Cure, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, 1760 Haygood Drive, Atlanta, GA 30322, USA
Ramyani De
Center for ViroScience and Cure, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, 1760 Haygood Drive, Atlanta, GA 30322, USA
Julia C. LeCher
Center for ViroScience and Cure, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, 1760 Haygood Drive, Atlanta, GA 30322, USA
Jessica A. Downs-Bowen
Center for ViroScience and Cure, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, 1760 Haygood Drive, Atlanta, GA 30322, USA
Shu Ling Goh
Center for ViroScience and Cure, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, 1760 Haygood Drive, Atlanta, GA 30322, USA
Keivan Zandi
Center for ViroScience and Cure, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, 1760 Haygood Drive, Atlanta, GA 30322, USA
Tamara McBrayer
Center for ViroScience and Cure, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, 1760 Haygood Drive, Atlanta, GA 30322, USA
Franck Amblard
Center for ViroScience and Cure, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, 1760 Haygood Drive, Atlanta, GA 30322, USA
Dharmeshkumar Patel
Center for ViroScience and Cure, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, 1760 Haygood Drive, Atlanta, GA 30322, USA
James J. Kohler
Center for ViroScience and Cure, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, 1760 Haygood Drive, Atlanta, GA 30322, USA
Manoj Bhasin
Center for Cystic Fibrosis & Airways Disease Research, Division of Pulmonary, Allergy & Immunology, Cystic Fibrosis and Sleep, Emory University and Children’s Healthcare of Atlanta, 2015 Uppergate Drive, Atlanta, GA 30322, USA
Brian S. Dobosh
Center for Cystic Fibrosis & Airways Disease Research, Division of Pulmonary, Allergy & Immunology, Cystic Fibrosis and Sleep, Emory University and Children’s Healthcare of Atlanta, 2015 Uppergate Drive, Atlanta, GA 30322, USA
Vikas Sukhatme
Morningside Center for Innovative and Affordable Medicine, Departments of Medicine and Hematology and Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA
Rabindra M. Tirouvanziam
Center for Cystic Fibrosis & Airways Disease Research, Division of Pulmonary, Allergy & Immunology, Cystic Fibrosis and Sleep, Emory University and Children’s Healthcare of Atlanta, 2015 Uppergate Drive, Atlanta, GA 30322, USA
Raymond F. Schinazi
Center for ViroScience and Cure, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, 1760 Haygood Drive, Atlanta, GA 30322, USA
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.
