新聞

The Global Phosphorylation Landscape of SARS-CoV-2 Infection

The causative agent of the coronavirus disease 2019 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected millions and killed hundreds of thousands of people worldwide, highlighting an urgent need to develop antiviral therapies. Here we present a quantitative mass spectrometry-based phosphoproteomics survey of SARS-CoV-2 infection in Vero E6 cells, revealing dramatic rewiring of phosphorylation on host and viral proteins. SARS-CoV-2 infection promoted casein kinase II (CK2) and p38 MAPK activation, production of diverse cytokines, and shutdown of mitotic kinases, resulting in cell cycle arrest. Infection also stimulated a marked induction of CK2-containing filopodial protrusions possessing budding viral particles. Eighty-seven drugs and compounds were identified by mapping global phosphorylation profiles to dysregulated kinases and pathways. We found pharmacologic inhibition of the p38, CK2, CDK, AXL, and PIKFYVE kinases to possess antiviral efficacy, representing potential COVID-19 therapies.
 
Silmitasertib, an inhibitor of CSNK2A1 and CSNK2A2, was found to possess antiviral activity (IC50 = 2.34 mM; Figures 7C and S5). In conjunction with data supporting physical interaction (Gordon et al., 2020) and colocalization with N protein (Figure 5F), as well as a potential role in remodeling extracellular matrix upon infection (Figures 5 and S3), CK2 signaling appears to be an important pathway hijacked by SARS-CoV-2. Furthermore, silmitasertib is currently being considered for human testing as a potential treatment for COVID-19.

 
We tested 68 drugs and compounds and found antiviral activity for several that are FDA approved, in clinical testing, or under preclinical development for various diseases, including silmitasertib (CK2, phase 2), gilteritinib (AXL, FDA approved), ARRY-797 (p38, phase 2/3), MAPK13-IN-1 (p38, preclinical), SB203580 (p38, preclinical), ralimetinib (p38, phase 2), apilimod (PIKFYVE, phase 1), and dinaciclib (CDK, phase 3), among others (Figure S5; Table S8). Silmitasertib, a small molecule undergoing clinical trials for various cancers, is now being considered for testing in humans to combat COVID-19. Although the effectiveness of CK2 inhibition may be attributed to its regulation of stress granules (Gordon et al., 2020), viral egress and dissemination could be facilitated by CK2-mediated remodeling of the extracellular matrix (Figure 5).
 


期刊連結 
https://www.cell.com/cell/fulltext/S0092-8674(20)30811-4