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

被引:4
|
作者
Ravindran, Vandana [1 ,2 ]
Wagoner, Jessica [3 ]
Athanasiadis, Paschalis [2 ,4 ]
Den Hartigh, Andreas B. [3 ]
Sidorova, Julia M. [3 ]
Ianevski, Aleksandr [5 ]
Fink, Susan L. [3 ]
Frigessi, Arnoldo [4 ]
White, Judith [6 ,7 ]
Polyak, Stephen J. [3 ]
Aittokallio, Tero [4 ,8 ,9 ]
机构
[1] Univ Oslo, Oslo Ctr Biostat & Epidemiol OCBE, Oslo, Norway
[2] Oslo Univ Hosp, Inst Canc Res, Oslo, Norway
[3] Univ Washington, Dept Lab Med & Pathol, 325 9th Ave Box 359690, Seattle, WA 98104 USA
[4] Univ Oslo, OCBE, Oslo, Norway
[5] Univ Helsinki, FIMM, HiLIFE, Helsinki, Finland
[6] Univ Virginia, Dept Cell Biol, Charlottesville, VA 22903 USA
[7] Univ Virginia, Dept Microbiol, Charlottesville, VA 22903 USA
[8] Univ Helsinki, Inst Canc Res, Helsinki, Finland
[9] Univ Helsinki, HiLIFE Unit, FIMM, Helsinki, Finland
基金
芬兰科学院;
关键词
cell context specificity; host modulators; network prioritization; protein-protein interactions; SARS-CoV-2; HIV;
D O I
10.1093/bib/bbac456
中图分类号
Q5 [生物化学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页数:14
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