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The SKI Complex Is a Broad-Spectrum, Host-Directed Antiviral Drug Target for Coronaviruses, Influenza, and Filoviruses

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The SKI Complex Is a Broad-Spectrum, Host-Directed Antiviral Drug Target for Coronaviruses, Influenza, and Filoviruses The SKI complex is a broad-spectrum, host-directed antiviral drug target for coronaviruses, influenza, and filoviruses Stuart Westona, Lauren Baraccoa, Chloe Kellera, Krystal Matthewsa, Marisa E. McGratha, James Loguea, Janie Liangb, Julie Dyallb, Michael R. Holbrookb, Lisa E. Hensleyb, Peter B. Jahrlingb,c, Wenbo Yud,e, Alexander D. MacKerell Jrd,e, and Matthew B. Friemana,1 aDepartment of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201; bIntegrated Research Facility, National Institute of Allergy and Infectious Diseases, NIH, Frederick, MD 21702; cEmerging Viral Pathogens Section, National Institute of Allergy and Infectious Diseases, NIH, Frederick, MD 21702; dCenter for Biomolecular Therapeutics, University of Maryland School of Medicine, Baltimore, MD 21201; and eUniversity of Maryland Computer-Aided Drug Design Center, Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD 21201 Edited by Peter Palese, Icahn School of Medicine at Mount Sinai, New York, NY, and approved October 11, 2020 (received for review June 23, 2020) The SARS-CoV-2 pandemic has made it clear that we have a des- broader role in viral replication. These findings suggest that the perate need for antivirals. We present work that the mammalian SKI complex could impact mammalian virus replication, but the SKI complex is a broad-spectrum, host-directed, antiviral drug tar- picture is far from clear. get. Yeast suppressor screening was utilized to find a functional Using yeast suppressor screening, we identified that influenza A genetic interaction between proteins from influenza A virus (IAV) virus (IAV) NS1 and Middle East respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus (MERS-CoV) with (MERS-CoV) ORF4a proteins have a genetic interaction with the eukaryotic proteins that may be potential host factors involved in SKI complex. Finding that both viral proteins have a genetic in- replication. This screening identified the SKI complex as a potential teraction with the yeast SKI complex we subsequently determined host factor for both viruses. In mammalian systems siRNA-mediated that siRNA knockdown of the human SKI complex resulted in knockdown of SKI genes inhibited replication of IAV and MERS-CoV. significant reduction in replication of these two distinct viruses, MICROBIOLOGY In silico modeling and database screening identified a binding suggesting the complex may be a broad-spectrum antiviral target. pocket on the SKI complex and compounds predicted to bind. Ex- Using the site identification by ligand competitive saturation perimental assays of those compounds identified three chemical (SILCS) in silico modeling approach (12) we identified a binding structures that were antiviral against IAV and MERS-CoV along with pocket on one of the subunits of the SKI complex and used this the filoviruses Ebola and Marburg and two further coronaviruses, to screen for compounds with antiviral activity. From the se- SARS-CoV and SARS-CoV-2. The mechanism of antiviral activity is lected compounds, experimental assays were used to identify through inhibition of viral RNA production. This work defines the three unique chemical compounds that were capable of inhibit- mammalian SKI complex as a broad-spectrum antiviral drug target and identifies lead compounds for further development. ing both IAV and MERS-CoV replication. Further experimental analyses show that the mechanism of antiviral action is through broad-spectrum antiviral | coronavirus | influenza | filovirus | antiviral host inhibition of viral RNA production. Moreover, our lead com- factor pound was found to inhibit replication of the filoviruses Ebola and Marburg, extending the broad-spectrum activity to a third viral family that causes significant human morbidity and t the end of 2019 cases of pneumonia of unknown etiology Awere identified in China. In the first week of January, a novel coronavirus was identified as the cause and was found to Significance be spreading between people. In the months since, the virus has spread around the world with over 40 million cases by October The SARS-CoV-2 pandemic of 2020 has highlighted the great 2020. Among many things that the SARS-CoV-2 (severe acute need for antiviral therapeutics. In this work, we identify a host respiratory syndrome coronavirus-2) outbreak has demonstrated factor, the SKI complex, is involved in replication of influenza is the immense need for both specific and broadly acting antiviral and coronaviruses. Using computational modeling we were therapeutics to treat known viruses and those yet to emerge in able to identify chemicals that interact with the host factor that the human population. display broad-spectrum antiviral activity against influenza, Here, we detail work identifying the SKI complex as a po- coronaviruses, and filoviruses, all of which cause significant tential broad-spectrum, host-directed, antiviral target. The SKI morbidity and mortality. Broad-spectrum antiviral therapeutics complex is an RNA helicase and a cofactor for the cytosolic RNA are sorely needed to combat known and unknown viral path- exosome involved in various aspects of RNA metabolism (1–4). ogens and the work presented here is our first step to devel- The SKI complex was originally identified in yeast as a result of oping antivirals to target the SKI complex. the super killer (SKI) phenotype (5). In this phenotype, knockout Author contributions: S.W., J. Liang, J.D., M.R.H., L.E.H., P.B.J., W.Y., A.D.M., and M.B.F. of the yeast SKI genes allows production of a viral toxin that kills designed research; S.W., L.B., C.K., K.M., M.E.M., J. Logue, J. Liang, J.D., M.R.H., L.E.H., yeast cells; when present, the SKI complex degrades the viral P.B.J., W.Y., A.D.M., and M.B.F. performed research; S.W. analyzed data; and S.W. and RNA (6). The cytosolic RNA exosome has been suggested to have M.B.F. wrote the paper. a role in replication of mammalian viruses such as influenza (7) The authors declare no competing interest. and hepatitis B (8, 9). The TRAMP complex has a similar function This article is a PNAS Direct Submission. to the SKI complex but acts as a nuclear cofactor of the RNA Published under the PNAS license. exosome. This protein complex has been linked to replication of 1To whom correspondence may be addressed. Email: [email protected]. multiple RNA viruses (10). Additionally, the enzymatic subunit of This article contains supporting information online at https://www.pnas.org/lookup/suppl/ the SKI complex, SKIV2L, has been suggested to regulate the IFN doi:10.1073/pnas.2012939117/-/DCSupplemental. response by modulating RIG-I (11), which could point toward a www.pnas.org/cgi/doi/10.1073/pnas.2012939117 PNAS Latest Articles | 1of12 Downloaded by guest on September 29, 2021 mortality. Finally, we found that our lead compound has broad These compounds will act as the basis of structure–activity re- anticoronavirus activity, inhibiting severe acute respiratory syn- lationship studies in the search for more potent compounds with drome coronavirus (SARS-CoV) and SARS-CoV-2 replication. the potential to be developed into therapeutic agents. Devel- Our work identifies a host factor involved in the replication of oping broad-spectrum antivirals that target both the viruses coronaviruses, influenza, and filoviruses. We have identified themselves and the host they infect, that can be used in combi- multiple chemical scaffolds that are modeled to interact with the nation, may be the best approach to prepare for the next viral SKI complex, and all show broad-spectrum antiviral activity. disease outbreak. Fig. 1. Yeast suppressor screening identifies the SKI complex as a suppressor of NS1 and ORF4a-mediated slow growth. (A) Yeast knockouts for each component of the SKI complex were transformed with the NS1 galactose-inducible expression plasmid or empty vector control (EV). Growth rate of these yeast was measured over a 48 h culture period. Mean OD600 between three independent colonies in two independent experiments is plotted with error bars being the SD. (B)AsinA, but with an ORF4a expression plasmid. (C) HEK293T cells were cotransfected with plasmids to express HA-tagged human SKI genes (SKIV2L-HA, TTC37-HA, or WDR61-HA) with either IAV NS1-GFP or MERS-CoV ORF4a-GFP. After transfection, cells were lysed with RIPA lysis buffer and used to analyze whole cell lysate (WCL) or protein was used for HA immunoprecipitation, analyzing nonspecific bead binding (NS), flow through for unbound protein (FT) and the immunopreciptate (IP). In all cases, samples were separated by SDS/PAGE and Western blotted (WB) for GFP, HA, or tubulin (as loading and immunoprecipitation clearance control). 2of12 | www.pnas.org/cgi/doi/10.1073/pnas.2012939117 Weston et al. Downloaded by guest on September 29, 2021 Results scrambled control, or were mock transfected for 3 d, prior to The SKI Complex Has a Genetic Interaction with IAV NS1 and MERS-CoV being infected with each virus for 24 h (multiplicity of infection ORF4a. We have previously demonstrated that certain MERS-CoV [MOI] 0.01 and MOI 0.1 for IAV and MERS-CoV, respectively). proteins are capable of causing slow growth when expressed in the After the infection, virus was collected and titered. yeast Saccharomyces cerevisiae (13). In addition to MERS-CoV, Both siRNA sequences against SKIV2L and TTC37 gave a proteins encoded by IAV are capable of causing a slow growth significant reduction in IAV replication (Fig. 2A). The knockdown phenotype in S. cerevisiae (SI Appendix,Fig.S1A; 14). We focused of WDR61 with one sequence also gave a significant reduction, our attention on the NS1 protein as we had previously validated its while the other gave a significant enhancement in replication of slow growth phenotype (14) and it has similarity to MERS-CoV IAV (Fig. 2A). For MERS-CoV, all but one of the siRNA se- ORF4a (the subject of our previous study) in being a double- quences caused a significant reduction in replication (Fig.
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