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

ABSTRACT: 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.

SUBMITTER: Goswami R

PROVIDER: S-EPMC8579697 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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

Goswami Ria R Russell Veronica S VS Tu Joshua J JJ Thomas Charlene C Hughes Philip P Kelly Francine F Langel Stephanie N SN Steppe Justin J Palmer Scott M SM Haystead Timothy T Blasi Maria M Permar Sallie R SR

iScience 20211110 12

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 progress ...[more]

PMID: 34786537

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Project description:ObjectivesSingle-agent heat shock protein 90 (HSP90) inhibition has demonstrated activity in oncogene-driven non-small cell and small cell lung cancers. SNX-5422 is an oral HSP90 inhibitor with increased activity in vitro with the addition of carboplatin and paclitaxel. Therefore, we conducted a phase 1, open-label, multicenter study to evaluate SNX-5422, carboplatin and paclitaxel followed by SNX-5422 maintenance in patients with advanced lung cancers.Materials and methodsIn part 1 (3 + 3 dose escalation), SNX-5422 (50/75/100-mg/m2) was dosed every other day (qod) for 21 days (28-day cycle) for ≤4 cycles; carboplatin (AUC 5)-paclitaxel (175 mg/m2) was administered once every 3 weeks for ≤6 courses. In part 2 (maintenance), subjects who achieved at least stable disease in part 1 received 100 mg/m2 SNX-5422 monotherapy qod for 21 days (28-day cycle).ResultsTwenty-three patients with advanced non-small cell lung cancer (NSCLC, n = 20) and small cell lung cancer (SCLC, n = 3) were enrolled. The median age was 60 years and 61% (n = 14/23) had ≥1 prior treatment regimens. The maximum tolerated dose of SNX-5422 was 100 mg/m2 qod in combination with carboplatin-paclitaxel. The most common treatment-related grade 3/4 adverse events (part 1/part 2) were diarrhea (26%/15%) and nausea (9%/0%). In response-evaluable patients with NSCLC, 33% (6/18) had a partial response, 56% (10/18) stable disease, and 11% (2/18) progressive disease. Patients who remained on single-agent SNX-5422 maintenance therapy ≥2 months (n = 9) had cancers enriched for oncogenic drivers (n = 3 KRAS mutation, n = 1 EGFR exon 20 mutation, n = 1 HER2 mutation, and n = 1 RET fusion).ConclusionsThe triplet combination of SNX-5422, carboplatin and paclitaxel followed by maintenance SNX-5422 therapy was well-tolerated and showed anti-tumor activity. Cancers for which disease control on single-agent SNX-5422 maintenance was observed were enriched for oncogene-driven NSCLCs.

Project description:Purpose: In addition to developing antivirals targeting specific SARS-CoV-2 viral proteins, there has been a growing effort in developing therapeutics targeting host proteins exploited by SARS-CoV-2 for their replication or implicated in viral pathogenesis. As such therapeutics can impair normal functioning of host proteins, a clear understanding of their impact on cellular mechanisms is critically important. Here, we characterized the interactions of a host-targeted anti-SARS-CoV-2 therapeutic, SNX-5422, with the cellular machinery using a physiologically relevant ex vivo human primary tracheobronchial epithelial (TBE) cell model. Methods: Fully differentiated human TBE cells (EpiAirwayTM) from 3 independent donors with no reported respiratory disease or smoking history were obtained from MatTek (Ashland, MA). The cells were cultured at the air-liquid interface in 1 ml of AIR-100-MM culture medium (MatTek) in 6 well plates at 37°C in 5% CO2. Upon receipt of cells, the cultures were acclimated for 16-24hr prior to the start of experiments. Human TBE cells from each donor were treated with 1µM SNX-5422 or 0.1% DMSO added to the media on the basolateral side of the culture, in three biological replicates. After 48hrs, cells were resuspended in TRIzol reagent (Thermo Fisher) and total RNA from the cells was extracted by phase separation with chloroform and subsequently using the RNeasy Mini Kit (Qiagen). RNA-Seq libraries were prepared using TruSeq RNA library Prep Kit v2 (Illumina, Inc. USA). Before pooling and sequencing, fragment length distribution and library quality were assessed on a TapeStation 2200 (Agilent Technologies), and the libraries were validated by Qubit Fluorometers (Thermo Fisher). All libraries were then pooled in a concentration at 4nM and sequenced in quadruplets on a NextSeq 500 Illumina sequencing platform system using NextSeq 500/550 High Output Kit v2.0 (150 cycles) (Illumina, Inc. USA). Conclusion: This study identified differentially expressed genes between DMSO-treated and SNX-5422-treated human TBE cells.

Dataset Information

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

Publications

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

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