Discovery of host-directed modulators of virus infection by probing the SARS-CoV-2–host protein–protein interaction network

Abstract

The ongoing coronavirus disease 2019 (COVID-19) pandemic has highlighted the need to better understand virus–host interactions. We developed a network-based method that expands the severe acute respiratory syndrome coronavirus-2 (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 the host proteins HDAC2, BRD4 and USP10 have antiviral functions. We observed marked differences in antiviral effects across cell lines, which may have consequences for identification of selective modulators of viral infection or potential antiviral therapeutics. While network-based approaches enable systematic identification of host targets and selective compounds that may modulate the SARS-CoV-2 interactome, further developments are warranted to increase their accuracy and cell-context specificity.

Role of E3 ubiquitin ligases and deubiquitinating enzymes in SARS-CoV-2 infection

“…For example, as a protein that interacts with SARS-CoV-2, ubiquitin-specific peptidase 13 (USP13) displays a considerably high incidence of genomic alterations within immune cells of SARS-CoV-2 patients (Süt, 2020). Although USP13 assumes an antiviral role during the pathogenesis of SARS-CoV-2 (Ravindran et al, 2022), some contend that in specific scenarios, USP13 not only fails to impart antiviral effects but instead stimulates viral invasion. This is due to their discovery that SARS-CoV-2 hijacks the host's USP13 to impede nsp13 degradation through ubiquitination, resulting in obstruction of antiviral constituents' functionality and inhibition of type I IFN production (Guo et al, 2021).…”