Oral Hsp90 Inhibitor, SNX-5422, Attenuates SARS-CoV-2 Replication and Dampens Inflammation in Airway Cells

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

doi:10.2139/ssrn.3803615

Cited by 8 publications

(9 citation statements)

References 30 publications

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“…The repurposing of several other candidate drugs is supported by previous studies. For example, SNX‐5422, targeting endoplasmin (HSP90B1), which is in charge of protein processing in the ER (Figs 4C and 5C), was suggested for use as an oral post‐exposure prophylactic or early‐phase therapeutic for SARS‐CoV‐2 infection (preprint: Goswami et al , 2021). The Ras‐related proteins RAB1 and RAB7 are involved in the endocytic pathway (Fig 4C), and their activation is modulated to facilitate SARS‐CoV‐2 entry and intracellular survival (Sicari et al , 2020; Daniloski et al , 2021).…”

Section: Resultsmentioning

confidence: 99%

SARS‐CoV‐2–host proteome interactions for antiviral drug discovery

Liu

Huuskonen

Laitinen

et al. 2021

Molecular Systems Biology

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Treatment options for COVID-19, caused by SARS-CoV-2, remain limited. Understanding viral pathogenesis at the molecular level is critical to develop effective therapy. Some recent studies have explored SARS-CoV-2-host interactomes and provided great resources for understanding viral replication. However, host proteins that functionally associate with SARS-CoV-2 are localized in the corresponding subnetwork within the comprehensive human interactome. Therefore, constructing a downstream network including all potential viral receptors, host cell proteases, and cofactors is necessary and should be used as an additional criterion for the validation of critical host machineries used for viral processing. This study applied both affinity purification mass spectrometry (AP-MS) and the complementary proximity-based labeling MS method (BioID-MS) on 29 viral ORFs and 18 host proteins with potential roles in viral replication to map the interactions relevant to viral processing. The analysis yields a list of 693 hub proteins sharing interactions with both viral baits and host baits and revealed their biological significance for SARS-CoV-2. Those hub proteins then served as a rational resource for drug repurposing via a virtual screening approach. The overall process resulted in the suggested repurposing of 59 compounds for 15 protein targets. Furthermore, antiviral effects of some candidate drugs were observed in vitro validation using image-based drug screen with infectious SARS-CoV-2. In addition, our results suggest that the antiviral activity of methotrexate could be associated with its inhibitory effect on specific protein-protein interactions.

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Section: Resultsmentioning

confidence: 99%

SARS‐CoV‐2–host proteome interactions for antiviral drug discovery

Liu

Huuskonen

Laitinen

et al. 2021

Molecular Systems Biology

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“…Intestinally, it has been shown that PGLYRP4 expression could be stimulated by TLR3 ligand polyI: C as a synthetic viral double-stranded RNA (dsRNA), which suggests a potential immunomodulatory role of PGLYRP4 in response to viral components in addition to its previous anti-bacterial properties [83]. As mentioned earlier, the dysregulation of PGLYRP4 in the NHBC cell line has been reported by previous in silico studies performing DEG analysis on the GSE147507 dataset [84][85][86][87][88]. Intriguingly, a recent in vitro study showed that treatment with an Hsp90 inhibitor, SNX-5422, exerts promising effects in inhibiting SARS-CoV-2 replication as well as regulating the expression of host factors involved in innate immunity such as PGLYRP4.…”

Section: Discussionmentioning

confidence: 64%

Weighted Gene Co-Expression Network Analysis Combined with Machine Learning Validation to Identify Key Modules and Hub Genes Associated with SARS-CoV-2 Infection

Karami

Derakhshani

GhasemiGol

et al. 2021

JCM

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The coronavirus disease-2019 (COVID-19) pandemic has caused an enormous loss of lives. Various clinical trials of vaccines and drugs are being conducted worldwide; nevertheless, as of today, no effective drug exists for COVID-19. The identification of key genes and pathways in this disease may lead to finding potential drug targets and biomarkers. Here, we applied weighted gene co-expression network analysis and LIME as an explainable artificial intelligence algorithm to comprehensively characterize transcriptional changes in bronchial epithelium cells (primary human lung epithelium (NHBE) and transformed lung alveolar (A549) cells) during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Our study detected a network that significantly correlated to the pathogenicity of COVID-19 infection based on identified hub genes in each cell line separately. The novel hub gene signature that was detected in our study, including PGLYRP4 and HEPHEL1, may shed light on the pathogenesis of COVID-19, holding promise for future prognostic and therapeutic approaches. The enrichment analysis of hub genes showed that the most relevant biological process and KEGG pathways were the type I interferon signaling pathway, IL-17 signaling pathway, cytokine-mediated signaling pathway, and defense response to virus categories, all of which play significant roles in restricting viral infection. Moreover, according to the drug–target network, we identified 17 novel FDA-approved candidate drugs, which could potentially be used to treat COVID-19 patients through the regulation of four hub genes of the co-expression network. In conclusion, the aforementioned hub genes might play potential roles in translational medicine and might become promising therapeutic targets. Further in vitro and in vivo experimental studies are needed to evaluate the role of these hub genes in COVID-19.

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“…The range of MOIs was chosen based on previously established models of infection kinetics. 64 After 1 hour incubation, cells were washed with PBS and then incubated with fresh culture medium for 24, 48 and 72 hours. Phase contrast images of the infected podocytes revealed changes in cell morphology at higher MOI compared to mock (Supplementary Figure 1A).…”

Section: Live Sars-cov-2 Virus Infects and Replicates In Human Ips Cell-derived Podocytesmentioning

confidence: 99%

“…Ten-fold dilutions of each cell supernatant were assed in duplicates as previously described. 64 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. (Figure 3D).…”

Section: Live Sars-cov-2 Virus Infects and Replicates In Human Ips Cell-derived Podocytesmentioning

confidence: 99%

BSG/CD147 and ACE2 receptors facilitate SARS-CoV-2 infection of human iPS cell-derived kidney podocytes

Kalejaiye

Bhattacharya

Burt

et al. 2021

Preprint

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BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the Coronavirus disease 2019 (COVID-19), which was declared a pandemic by the World Health Organization (WHO) in March 2020. The disease has caused more than 5.1 million deaths worldwide. While cells in the respiratory system are frequently the initial target for SARS-CoV-2, clinical studies suggest that COVID-19 can become a multi-organ disease in the most severe cases. Still, the direct affinity of SARS-CoV-2 for cells in other organs such as the kidneys, which are often affected in severe COVID-19, remains poorly understood.MethodIn this study, we employed a human induced pluripotent stem (iPS) cell-derived model to investigate the affinity of SARS-CoV-2 for kidney glomerular podocytes. We studied uptake of the live SARS-CoV-2 virus as well as pseudotyped viral particles by human iPS cell derived podocytes using qPCR, western blot, and immunofluorescence. Global gene expression and qPCR analyses revealed that human iPS cell-derived podocytes express many host factor genes (including ACE2, BSG/CD147, PLS3, ACTR3, DOCK7, TMPRSS2, CTSL CD209, and CD33) associated with SARS-CoV-2 binding and viral processing.ResultInfection of podocytes with live SARS-CoV-2 or spike-pseudotyped lentiviral particles revealed viral uptake by the cells at low Multiplicity of Infection (MOI of 0.01) as confirmed by RNA quantification and immunofluorescence studies. Our results also indicate 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. Additionally, antibody blocking experiments identified BSG/CD147 and ACE2 receptors as key mediators of spike binding activity in human iPS cell-derived podocytes.ConclusionThese results show that SARS-CoV-2 can infect kidney glomerular podocytes in vitro. These results also show that the uptake of SARS-CoV-2 by kidney podocytes occurs 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.Significant statementMany patients with COVID19 disease exhibit multiorgan complications, suggesting that SARS-CoV-2 infection can extend beyond the respiratory system. Acute kidney injury is a common COVID-19 complication contributing to increased morbidity and mortality. Still, SARS-Cov-2 affinity for specialized kidney cells remain less clear. By leveraging our protocol for stem cell differentiation, we show that SARS-CoV-2 can directly infect kidney glomerular podocytes by using multiple Spike-binding proteins including ACE2 and BSG/CD147. Our results also indicate that infection by SARS-CoV-2 virus can cause podocyte cell death and foot process effacement, a hallmark of podocytopathies including collapsing glomerulopathy observed in patients with severe COVID-19 disease. 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 8 publications

References 30 publications

SARS‐CoV‐2–host proteome interactions for antiviral drug discovery

SARS‐CoV‐2–host proteome interactions for antiviral drug discovery

Weighted Gene Co-Expression Network Analysis Combined with Machine Learning Validation to Identify Key Modules and Hub Genes Associated with SARS-CoV-2 Infection

BSG/CD147 and ACE2 receptors facilitate SARS-CoV-2 infection of human iPS cell-derived kidney podocytes

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