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

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

doi:10.1016/j.isci.2021.103412

Cited by 24 publications

(20 citation statements)

References 85 publications

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“…In human cell lines infected with SARS-CoV and SARS-CoV-2, HSP90 inhibition resulted in reduction of viral replication, which suggests its involvement in infection []. Taking into account recent studies pointing out HSP90 as a potential target in COVID-19 treatment [ 72 , 73 , 74 , 75 ], this finding especially supports the value of presented here results.…”

Section: Discussionsupporting

confidence: 92%

Thrombosis-related circulating miR-16-5p is associated with disease severity in patients hospitalised for COVID-19

et al. 2022

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SARS-CoV-2 tropism for the ACE2 receptor, along with the multifaceted inflammatory reaction, is likely to drive the generalized hypercoagulable and thrombotic state seen in patients with COVID-19. Using the original bioinformatic workflow and network medicine approaches we reanalysed four coronavirus-related expression datasets and performed co-expression analysis focused on thrombosis and ACE2 related genes. We identified microRNAs (miRNAs) which play role in ACE2-related thrombosis in coronavirus infection and further, we validated the expressions of precisely selected miRNAs-related to thrombosis (miR-16-5p, miR-27a-3p, let-7b-5p and miR-155-5p) in 79 hospitalized COVID-19 patients and 32 healthy volunteers by qRT-PCR. Consequently, we aimed to unravel whether bioinformatic prioritization could guide selection of miRNAs with a potential of diagnostic and prognostic biomarkers associated with disease severity in patients hospitalized for COVID-19. In bioinformatic analysis, we identified EGFR, HSP90AA1, APP, TP53, PTEN, UBC, FN1, ELAVL1 and CALM1 as regulatory genes which could play a pivotal role in COVID-19 related thrombosis. We also found miR-16-5p, miR-27a-3p, let-7b-5p and miR-155-5p as regulators in the coagulation and thrombosis process. In silico predictions were further confirmed in patients hospitalized for COVID-19. The expression levels of miR-16-5p and let-7b in COVID-19 patients were lower at baseline, 7-days and 21-day after admission compared to the healthy controls (p < 0.0001 for all time points for both miRNAs). The expression levels of miR-27a-3p and miR-155-5p in COVID-19 patients were higher at day 21 compared to the healthy controls (p = 0.007 and p < 0.001, respectively). A low baseline miR-16-5p expression presents predictive utility in assessment of the hospital length of stay or death in follow-up as a composite endpoint (AUC:0.810, 95% CI, 0.71–0.91, p < 0.0001) and low baseline expression of miR-16-5p and diabetes mellitus are independent predictors of increased length of stay or death according to a multivariate analysis (OR: 9.417; 95% CI, 2.647–33.506; p = 0.0005 and OR: 6.257; 95% CI, 1.049–37.316; p = 0.044, respectively). This study enabled us to better characterize changes in gene expression and signalling pathways related to hypercoagulable and thrombotic conditions in COVID-19. In this study we identified and validated miRNAs which could serve as novel, thrombosis-related predictive biomarkers of the COVID-19 complications, and can be used for early stratification of patients and prediction of severity of infection development in an individual. Abbreviations: ACE2, angiotensin-converting enzyme 2AF, atrial fibrillationAPP, Amyloid Beta Precursor ProteinaPTT, activated partial thromboplastin timeAUC, Area under the curveAβ, amyloid betaBMI, body mass indexCAD, coronary artery diseaseCALM1, Calmodulin 1 geneCaM, calmodulinCCND1, Cyclin D1CI, confidence intervalCOPD, chronic obstructive pulmonary diseaseC...

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Section: Discussionsupporting

confidence: 92%

Thrombosis-related circulating miR-16-5p is associated with disease severity in patients hospitalised for COVID-19

et al. 2022

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“…Wyler et al demonstrated that inhibition of Hsp90 activity by onalespib, ganetespib, or 17-AAG resulted in a reduction of both SARS-CoV-2 replication and expression of pro-inflammatory cytokines in primary human airway epithelial cells (22). Similar results were obtained by Goswami et al using the Hsp90 inhibitor SNX-5422 (23). In addition, in vitro experiments revealed inhibition of SARS-CoV-2 replication by the Hsp90 inhibitors 17-AAG and tanespimycin, respectively (24, 25).…”

Section: Hsp90/70 and Covid-19supporting

confidence: 52%

Targeting heat shock proteins 90 and 70: A promising remedy for both autoimmune bullous diseases and COVID-19

Kasperkiewicz

Tukaj

2022

Front. Immunol.

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Heat shock proteins (Hsps), including Hsp90 and Hsp70, are intra- and extracellular molecules implicated in cellular homeostasis and immune processes and are induced by cell stress such as inflammation and infection. Autoimmune bullous disorders (AIBDs) and COVID-19 represent potentially life-threatening inflammatory and infectious diseases, respectively. A significant portion of AIBDs remain refractory to currently available immunosuppressive therapies, which may represent a risk factor for COVID-19, and suffer from treatment side-effects. Despite advances in vaccination, there is still a need to develop new therapeutic approaches targeting SARS-CoV-2, especially considering vaccine hesitancy, logistical distribution challenges, and breakthrough infections. In this mini review, we briefly summarize the role of targeting Hsp90/70 as a promising double-edged sword in the therapy of AIBDs and COVID-19.

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“…To explore the susceptibility of human iPS cell-derived podocytes to live SARS-CoV-2, podocytes were incubated with SARS-CoV-2 strain USA-WA1/2020 at MOI of 0.01, 0.1 or 1.0 for 1 h. All steps with live virus were strictly performed in Duke’s BSL3 facility following the guidelines provided by Duke University’s Biosafety committee and the CDC. The range of MOIs chosen was based on previously established models of infection kinetics ( Goswami et al, 2021 ). After 1 h incubation, cells were washed with PBS and then incubated with fresh culture medium for 24, 48 and 72 h ( Supplementary Figure S1A ).…”

Section: Resultsmentioning

confidence: 99%

“…We next performed plaque assays to measure the amount of infectious SARS-CoV-2 particles released from infected podocytes ( Supplementary Figures S1E–G , respectively). Ten-fold dilutions of each cell supernatant were assessed in duplicates as previously described ( Goswami et al, 2021 ). The number of plaque forming units (PFU) was significantly higher in the cells infected with MOI of 0.1 at 72 h.p.i compared to 24 and 48 h.p.i.…”

Section: Resultsmentioning

confidence: 99%

SARS-CoV-2 Employ BSG/CD147 and ACE2 Receptors to Directly Infect Human Induced Pluripotent Stem Cell-Derived Kidney Podocytes

Kalejaiye

Bhattacharya

Burt

et al. 2022

Front. Cell Dev. Biol.

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the Coronavirus disease 2019 (COVID-19), which has resulted in over 5.9 million deaths worldwide. While cells in the respiratory system are the initial target of SARS-CoV-2, there is mounting evidence that COVID-19 is a multi-organ disease. Still, the direct affinity of SARS-CoV-2 for cells in other organs such as the kidneys, which are often targeted in severe COVID-19, remains poorly understood. We employed a human induced pluripotent stem (iPS) cell-derived model to investigate the affinity of SARS-CoV-2 for kidney glomerular podocytes, and examined the expression of host factors for binding and processing of the virus. We studied cellular uptake of the live SARS-CoV-2 virus as well as a pseudotyped virus. Infection of podocytes with live SARS-CoV-2 or spike-pseudotyped lentiviral particles revealed cellular uptake even at low multiplicity of infection (MOI) of 0.01. We found that direct infection of human iPS cell-derived podocytes by SARS-CoV-2 virus can cause cell death and podocyte foot process retraction, a hallmark of podocytopathies and progressive glomerular diseases including collapsing glomerulopathy observed in patients with severe COVID-19 disease. We identified BSG/CD147 and ACE2 receptors as key mediators of spike binding activity in human iPS cell-derived podocytes. These results show that SARS-CoV-2 can infect kidney glomerular podocytes in vitro via multiple binding interactions and partners, which may underlie the high affinity of SARS-CoV-2 for kidney tissues. This stem cell-derived model is potentially useful for kidney-specific antiviral drug screening and mechanistic studies of COVID-19 organotropism.

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

Cited by 24 publications

References 85 publications

Thrombosis-related circulating miR-16-5p is associated with disease severity in patients hospitalised for COVID-19

Thrombosis-related circulating miR-16-5p is associated with disease severity in patients hospitalised for COVID-19

Targeting heat shock proteins 90 and 70: A promising remedy for both autoimmune bullous diseases and COVID-19

SARS-CoV-2 Employ BSG/CD147 and ACE2 Receptors to Directly Infect Human Induced Pluripotent Stem Cell-Derived Kidney Podocytes

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