Oral Hsp90 inhibitor SNX-5422 attenuates SARS-CoV-2 replication and dampens inflammation in airway cells
Ria Goswami,
Veronica S. Russell,
Joshua J. Tu,
Charlene Thomas,
Philip Hughes,
Francine Kelly,
Stephanie N. Langel,
Justin Steppe,
Scott M. Palmer,
Timothy Haystead,
Maria Blasi,
Sallie R. Permar
Affiliations
Ria Goswami
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA; Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA
Veronica S. Russell
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA
Joshua J. Tu
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA
Charlene Thomas
Division of Biostatistics, Department of Population Health Sciences, Weill Cornell Medicine, New York 10065, USA
Philip Hughes
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
Francine Kelly
Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA
Stephanie N. Langel
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA; Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA
Justin Steppe
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA
Scott M. Palmer
Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA
Timothy Haystead
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA
Maria Blasi
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA; Division of Infectious Diseases, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA; Corresponding author
Sallie R. Permar
Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA; Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA; Corresponding author
Summary: Currently available SARS-CoV-2 therapeutics are targeted toward moderately to severely ill patients and require intravenous infusions, with limited options for exposed or infected patients with no or mild symptoms. Although vaccines have demonstrated protective efficacy, vaccine hesitancy and logistical distribution challenges will delay their ability to end the pandemic. Hence, there is a need for rapidly translatable, easy-to-administer-therapeutics that can prevent SARS-CoV-2 disease progression, when administered in the early stages of infection. We demonstrate that an orally bioavailable Hsp90 inhibitor, SNX-5422, currently in clinical trials as an anti-cancer therapeutic, inhibits SARS-CoV-2 replication in vitro at a high selectivity index. SNX-5422 treatment of human primary airway epithelial cells dampened expression of inflammatory pathways previously associated with poor SARS-CoV-2 disease outcomes. In addition, SNX-5422 interrupted expression of host factors demonstrated to be crucial for SARS-CoV-2 replication. Development of SNX-5422 as SARS-CoV-2-early-therapy will dampen disease severity, resulting in better clinical outcomes and reduced hospitalizations.
