ABSTRACT
ABSTRACT The ongoing coronavirus disease 2019 (COVID-19) pandemic has highlighted the need to better understand virus-host interactions. We developed a network-based algorithm that expands the SARS-CoV-2-host protein interaction network and identifies host targets that modulate viral infection. To disrupt the SARS-CoV-2 interactome, we systematically probed for potent compounds that selectively target the identified host proteins with high expression in cells relevant to COVID-19. We experimentally tested seven chemical inhibitors of the identified host proteins for modulation of SARS-CoV-2 infection in human cells that express ACE2 and TMPRSS2. Inhibition of the epigenetic regulators bromodomain-containing protein 4 (BRD4) and histone deacetylase 2 (HDAC2), along with ubiquitin specific peptidase (USP10), enhanced SARS-CoV-2 infection. Such proviral effect was observed upon treatment with compounds JQ1, vorinostat, romidepsin, and spautin-1, when measured by cytopathic effect and validated by viral RNA assays, suggesting that HDAC2, BRD4 and USP10 host proteins have antiviral functions. Mycophenolic acid and merimepodib, two inhibitors of inosine monophosphate dehydrogenase (IMPDH 1 and IMPDH 2), showed modest antiviral effects with no toxicity in mock-infected control cells. The network-based approach enables systematic identification of host-targets that selectively modulate the SARS-CoV-2 interactome, as well as reveal novel chemical tools to probe virus-host interactions that regulate virus infection. Synopsis Viruses exploit host machinery and therefore it is important to understand the virus-host dependencies to gain better insight of the key regulators of viral infection. Using a context-specific SARS-COV-2 PPI network, a computational framework was developed to identify host modulators of viral infection. Chromatin modifying host proteins HDAC2 and BRD4, along with deubiquitinating enzyme USP10, act as antiviral proteins. IMPDH inhibitors mycophenolic acid and merimipodib showed modest antiviral response to SARS-COV-2 infection, and no toxic effects. Cell context specificity is a critical factor when identifying selective modulators of viral infection and potential antiviral therapeutics. Topology-based network models cannot distinguish between host-proteins, the inhibition of which leads to either virus suppressive or enhancing effects.