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PXD018117-1 A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Purposing [Reanalysis: PXD018117]

ABSTRACT: An outbreak of the novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 170,000 people since the end of 2019, killed over 7,400, and caused worldwide social and economic disruption. SARS-CoV-2 infection has a mortality rate of 3.4% among confirmed cases, and there are currently no effective antiviral molecules or vaccines for its treatment or prevention. The search for effective antiviral treatments has recently highlighted host-directed strategies, however besides data describing viral interactions with cell surface receptors and activating proteases, the scientific community has little knowledge of the molecular details of SARS-CoV-2 infection. To shed light on the mechanisms used by SARS-CoV-2 to infect human cells, we have utilized affinity-purification mass spectrometry to globally profile physical host protein interactions for 26 viral proteins encoded in the SARS-CoV-2 genome, identifying 332 high confidence interactions. Among the human proteins, we identify many druggable human proteins targeted by existing FDA approved drugs that we are currently evaluating for efficacy in live SARS-CoV-2 infection assays. The identification of host-dependency factors mediating virus infection may provide key insights into effective molecular targets for developing broadly acting antiviral targets against SARS-CoV-2 and other deadly coronavirus strains. [Original project description]

ORGANISM(S): Cell Culture

SUBMITTER: Yasushi Ishihama

PROVIDER: RPXD034697 | JPOST Repository | Sat Mar 25 00:00:00 GMT 2023

REPOSITORIES: jPOST

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Project description:Despite the wide availability of several safe and effective vaccines that can prevent severe COVID-19 disease, the emergence of SARS-CoV-2 variants of concern (VOC) that can partially evade vaccine immunity remains a global health concern. In addition, the emergence of highly mutated and neutralization-resistant SARS-CoV-2 VOCs such as BA.1 and BA.5 that can partially or fully evade (1) many therapeutic monoclonal antibodies in clinical use underlines the need for additional effective treatment strategies. Here, we characterize the antiviral activity of GS-5245, Obeldesivir (ODV), an oral prodrug of the parent nucleoside GS-441524, which targets the highly conserved RNA-dependent viral RNA polymerase (RdRp). Importantly, we show that GS-5245 is broadly potent in vitro against alphacoronavirus HCoV-NL63, severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-related Bat-CoV RsSHC014, Middle East Respiratory Syndrome coronavirus (MERS-CoV), SARS-CoV-2 WA/1, and the highly transmissible SARS-CoV-2 BA.1 Omicron variant in vitro and highly effective as antiviral therapy in mouse models of SARS-CoV, SARS-CoV-2 (WA/1), MERS-CoV and Bat-CoV RsSHC014 pathogenesis. In all these models of divergent coronaviruses, we observed protection and/or significant reduction of disease metrics such as weight loss, lung viral replication, acute lung injury, and degradation in pulmonary function in GS-5245-treated mice compared to vehicle controls. Finally, we demonstrate that GS-5245 in combination with the main protease (Mpro) inhibitor nirmatrelvir had increased efficacy in vivo against SARS-CoV-2 compared to each single agent. We also evalulate the effect of antiviral therapy on host gene expression using RNAseq and show that therapeutic intervention reduces host inflammatory response as compared to vehicle controls during acute SARS-CoV-2 infection. Altogether, our data supports the continuing clinical evaluation of GS-5245 in humans infected with COVID-19, including as part of a combination antiviral therapy, especially in populations with the most urgent need for more efficacious and durable interventions.

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Dataset Information

PXD018117-1 A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Purposing [Reanalysis: PXD018117]

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