The coronavirus disease 2019 (COVID-19), which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has been reported in over 258 million people and caused the deaths of almost 5.2 million worldwide. The clinical manifestations of COVID-19 vary greatly from asymptomatic and mild upper airway disease to severe pneumonia, acute respiratory distress syndrome (ARDS), a multi-organ failure that ultimately leads to death.
Study: Oral Hsp90 inhibitor SNX-5422 attenuates SARS-CoV-2 replication and dampens inflammation in airway cells. Image Credit: PHOTOCREO Michal Bednarek / Shutterstock.com
Background
Recently, efforts have been made to characterize the pathogenesis of SARS-CoV-2 and identify both therapeutic and prophylactic approaches that could reduce disease severity, as well as improve clinical symptoms. Currently, repurposed small molecules such as remdesivir, virus-specific monoclonal antibodies, and immunomodulatory agents such as corticosteroids are available for the treatment of COVID-19; however, most of these treatments require intravenous (IV) infusions.
Additionally, the prophylactic vaccines against SARS-CoV-2 have been associated with logical distribution challenges, vaccine hesitancy, and robust protection. Therefore, there remains a need for rapidly translatable post-exposure prophylactic interventions that can be administered during early infection.
Recent in silico studies with Hsp90, which is a cellular chaperone protein heat shock protein, as a potential anti-SARS-CoV-2 target were carried out. Additionally, in a murine model of sepsis, Hsp90 inhibition was associated with reduced lung injury and pulmonary inflammation. Therefore, a clinical trial was launched to determine the efficacy of IV administered Hsp90 inhibitor ganetespib (ADX-1612) against SARS-CoV-2 infection.
An orally bioavailable Hsp90 inhibitor, SNX-5422, is currently in clinical trials for treating solid-state malignancies and lymphomas. This compound has been found to be well tolerated in humans and is not associated with causing immunosuppression or adverse effects.
A new study published in iScience evaluates the efficacy of SNX-5422 as a post-exposure prophylactic treatment. Furthermore, the authors of this study also mapped the interaction of SNX-5422 with primary human airway epithelial cells from uninfected individuals who had no history of smoking or respiratory disease.
About the study
The current study involved fully differentiated human primary tracheobronchial epithelial (TBE) cells that were collected from three independent donors with no reported smoking history and respiratory disease. The in vitro studies took place in African Green Monkey kidney epithelial cells (Vero E6) and human lung epithelial cells, Calu-3. Hsp90 was synthesized in-house and characterized using proton nuclear magnetic resonance (NMR) and liquid chromatography/mass spectrometry (LC/MS).
Thereafter, SARS-CoV-2 propagation and titering were conducted in Vero E6 cells. Subsequently, SARS-CoV-2 infection and treatment were achieved through both Vero E6 and Calu-3 cells. The cellular cytotoxicity was measured using flow cytometry.
The infectious viral titers were measured by plaque assay followed by quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) and immunofluorescence assays. Finally, bulk ribonucleic acid (RNA)-sequencing and analysis of the data from human TBE cells were carried out.
Study findings
The results of the current study indicated that SNX-5422 is capable of attenuating the intracellular viral nucleocapsid (NP) and proportion of NP+ cells in a dose-dependent manner in both cell lines. Additionally, treatment with SNX-5422 led to a reduction in cell-free infectious viral material, while simultaneously causing minimal cytotoxic effects and retaining a high selectivity index in suppressing viral replication.
The in vivo studies with human primary tracheobronchial epithelial (TBE) cells revealed differential expression of mostly protein-coding cellular genes upon treatment with SNX-4522. Out of these protein-coding genes, 470 genes were upregulated and 891 genes were downregulated.
Furthermore, several cellular signaling pathways were altered upon treatment with SNX-5422. Cellular inflammatory pathways such as the tumor necrosis factor (TNF), interleukin 17 (IL-17), nucleotide-binding oligomerization domain (NOD)-like receptor, cytokine-cytokine receptor interaction Th17 cell differentiation, and chemokine signaling pathways were among those that were downregulated by treatment with the drug.
The signaling pathways that were associated with the regulation of the cell cycle, cellular senescence, as well as certain metabolic pathways were also found to be downregulated. However, cellular pathways involved in physiological functions were found to be upregulated.
The results also indicated that 55 genes associated with SARS-CoV-2 pathogenesis and disease progression were regulated by SNX-5422. These included inflammatory genes that could be further categorized into chemokines, cytokines, chemokine-receptor ligands, TNF-alpha-induced protein, ILs, interferon (IFN)-induced proteins, and regulators of inflammatory response.
Therefore, early treatment with SNX-5422 could help mitigate SARS-CoV-2-associated hyper inflammation and improve clinical outcomes. Furthermore, SNX-5422 treatment was also found to downregulate five pro-inflammatory genes that were expressed in Calu-3 cells infected by SARS-CoV-2.
Conclusion
Taken together, the current study indicates that the early administration of SNX-5422 interferes with the replication machinery of SARS-CoV-2 and reduces virus-induced inflammation and severe disease. Since SNX-5422 is orally bioavailable, clinically tested, easy to administer, and rapidly translatable, it may serve as a broad-spectrum ready-to-deploy therapeutic that would not only help to curb the ongoing pandemic but also future infections caused by SARS-CoV-2 variants.
The current study had one limitation in that the antiviral properties of SNX-5422 were limited only to cell lines. Experimental validation in human models and in clinical trials is still required.
Journal reference:
- Goswami, R., Russell, V. S., Tu, J. J., et al. (2021). Oral Hsp90 inhibitor SNX-5422 attenuates SARS-CoV-2 replication and dampens inflammation in airway cells. iScience. doi:10.1016/j.isci.2021.103412.
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