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Oral Hsp90 inhibitor, SNX-5422, attenuates SARS-CoV-2 replication and dampens 2 inflammation in airway cells.

Ria Goswami, Veronica S. Russell, Joshua J. Tu, Philip Hughes, Francine Kelly, Stephanie N. Langel, Justin Steppe, Scott M. Palmer, Timothy Haystead, Maria Blasi and Sallie R. Permar
Abstract

Currently available SARS-CoV-2 therapeutics are targeted towards moderately to severely ill patients and require intravenous infusions, with limited options for exposed or infected patients with no or mild symptoms. While 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 associated with poor SARS-CoV-2 disease outcomes. Additionally, SNX-5422 interrupted expression of host factors that are crucial for SARS-CoV-2 replication machinery. Development of SNX-5422 as SARS-CoV-2-early-therapy will dampen disease severity, resulting in better clinical outcomes and reduced hospitalizations.

Keywords

SARS-CoV-2-WAI/2020 virus, SNX-5422, COVID-19, infection, viral replication, EpiAirway (AIR-100, RNA-seq, differentially expressed genes, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, cellular inflammatory pathways, IL-17 signaling, cytokine-cytokine receptor interaction, TNF-signaling, Th17 cell differentiation, NOD-like receptor, chemokine signaling, SNX-5422, regulation of cell cycle, cellular senescence, biosynthesis of amino acids, tryptophan metabolism, Hsp90 inhibitor, cellular - adhesion, apoptosis, cellular proliferation, heat shock protein, CCL20, CXCL1, CSF3, S100A8, CXCL5, IL36G, CXCL6, CXCL3, RSAD2, CX3CL1, IFI44L, IL19, SCGB3A1, CXCL8, S100A9, SPRR2A, SPRR2D, IFITM1, CXCL8, S100A9, SPRR2A, SPRR2D, IFITM1, CXCL2, SAA1, SAA2, IL32, MX2, IFI27, CD14, TNFAIP2, ISG15, S100A2, SERPINA3, KLHDC7B, MMP9, MUC5B, UBE2C, CMPK2, FCGBP, CENPI, MSMB, SERPINE1, BIRC5, BPIFA1, BUB1B, ID1, CENPF, BCL2A1, PI3, FOS, PGLYRP4, CHAC1, BUB1, CCNB2, BATF2, SERPINF2, MT2A, OLR1, EDN2

Materials Tested

SNX-5422, HSP90 inhibitor

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