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).
Ralimetinib is currently in phase 2 clinical trials for treatment of ovarian cancer (Patnaik et al., 2016
), and ARRY-797 is in phase 3 clinical trials for treatment of cardiomyopathy. The antiviral activity observed for gilteritinib, an FDA-approved drug for treatment of acute myeloid leukemia, is supported by involvement of another AXL inhibitor, bencentinib, in the RECOVERY COVID-19 clinical trial in the United Kingdom. AXL is known to regulate various intracellular signaling pathways (Allen et al., 2002
; Hafizi and Dahlbäck, 2006
), including Ras/ERK, PI3K, and p38 (Allen et al., 2002
); AXL inhibition here may contribute to the downregulation of p38 signaling. Apilimod, a PIKFYVE inhibitor, has been described in a recent study to have antiviral capacity (Ou et al., 2020
). Here we expand this into a mechanism of regulation by phosphorylation of PIKFYVE upon SARS-CoV-2 infection.
Similar to successful antiretroviral therapy for HIV, a combinatorial drug cocktail may be a viable treatment option for SARS-CoV-2 infection. Specifically, combining remdesivir with the kinase inhibitors identified in this study as well as with translation inhibitors and/or modulators of sigma-1 receptor (Gordon et al., 2020
) warrants further testing. Furthermore, pairing genetic and pharmacological perturbations in a systematic fashion could identify new combination therapy approaches and illuminate disease mechanisms.
The unbiased, global phosphoproteomics approaches used here highlight cellular processes hijacked during SARS-CoV-2 infection. To address the need for improved therapeutic strategies to fight COVID-19, we employed a data-driven approach by mapping phosphorylation profiles of dysregulated signaling pathways to drugs and compounds targeting those signaling pathways. We hope this paradigm can be employed in the future to find additional therapies for COVID-19 and other infectious diseases.
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