Este articulo es un Preprint
Los preprints son informes de investigación preliminares que no han sido certificados por revisión por pares. No deben considerarse para guiar la práctica clínica o los comportamientos relacionados con la salud y no deben publicarse en los medios como información establecida.
Los preprints publicados en línea permiten a los autores recibir comentarios rápidamente, y toda la comunidad científica puede evaluar de forma independiente el trabajo y responder adecuadamente. Estos comentarios se publican junto con los preprints para que cualquiera pueda leer y servir como una revisión pospublicación.
Discovery of host-directed modulators of virus infection by probing the SARSCoV-2-host protein-protein interaction network
Preprint
en En
| PREPRINT-BIORXIV
| ID: ppbiorxiv-494640
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 O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=80 SRC="FIGDIR/small/494640v1_ufig1.gif" ALT="Figure 1"> View larger version (31K) org.highwire.dtl.DTLVardef@653d14org.highwire.dtl.DTLVardef@8d1234org.highwire.dtl.DTLVardef@1a632faorg.highwire.dtl.DTLVardef@5ce4f6_HPS_FORMAT_FIGEXP M_FIG C_FIG 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. O_LIUsing a context-specific SARS-COV-2 PPI network, a computational framework was developed to identify host modulators of viral infection. C_LIO_LIChromatin modifying host proteins HDAC2 and BRD4, along with deubiquitinating enzyme USP10, act as antiviral proteins. C_LIO_LIIMPDH inhibitors mycophenolic acid and merimipodib showed modest antiviral response to SARS-COV-2 infection, and no toxic effects. C_LIO_LICell context specificity is a critical factor when identifying selective modulators of viral infection and potential antiviral therapeutics. C_LIO_LITopology-based network models cannot distinguish between host-proteins, the inhibition of which leads to either virus suppressive or enhancing effects. C_LI
cc_by_nc_nd
Texto completo:
1
Colección:
09-preprints
Base de datos:
PREPRINT-BIORXIV
Tipo de estudio:
Prognostic_studies
/
Systematic_reviews
Idioma:
En
Año:
2022
Tipo del documento:
Preprint