tetano
Editor, Senior Moderator
Proc Natl Acad Sci U S A
. 2020 Nov 12;202012939.
doi: 10.1073/pnas.2012939117. Online ahead of print.
The SKI complex is a broad-spectrum, host-directed antiviral drug target for coronaviruses, influenza, and filoviruses
Stuart Weston[SUP] 1 [/SUP], Lauren Baracco[SUP] 1 [/SUP], Chloe Keller[SUP] 1 [/SUP], Krystal Matthews[SUP] 1 [/SUP], Marisa E McGrath[SUP] 1 [/SUP], James Logue[SUP] 1 [/SUP], Janie Liang[SUP] 2 [/SUP], Julie Dyall[SUP] 2 [/SUP], Michael R Holbrook[SUP] 2 [/SUP], Lisa E Hensley[SUP] 2 [/SUP], Peter B Jahrling[SUP] 2 3 [/SUP], Wenbo Yu[SUP] 4 5 [/SUP], Alexander D MacKerell Jr[SUP] 4 5 [/SUP], Matthew B Frieman[SUP] 6 [/SUP]
Affiliations
Abstract
The SARS-CoV-2 pandemic has made it clear that we have a desperate need for antivirals. We present work that the mammalian SKI complex is a broad-spectrum, host-directed, antiviral drug target. Yeast suppressor screening was utilized to find a functional genetic interaction between proteins from influenza A virus (IAV) and Middle East respiratory syndrome coronavirus (MERS-CoV) with eukaryotic proteins that may be potential host factors involved in replication. This screening identified the SKI complex as a potential host factor for both viruses. In mammalian systems siRNA-mediated knockdown of SKI genes inhibited replication of IAV and MERS-CoV. In silico modeling and database screening identified a binding pocket on the SKI complex and compounds predicted to bind. Experimental assays of those compounds identified three chemical structures that were antiviral against IAV and MERS-CoV along with the filoviruses Ebola and Marburg and two further coronaviruses, SARS-CoV and SARS-CoV-2. The mechanism of antiviral activity is through inhibition of viral RNA production. This work defines the mammalian SKI complex as a broad-spectrum antiviral drug target and identifies lead compounds for further development.
Keywords: antiviral host factor; broad-spectrum antiviral; coronavirus; filovirus; influenza.
. 2020 Nov 12;202012939.
doi: 10.1073/pnas.2012939117. Online ahead of print.
The SKI complex is a broad-spectrum, host-directed antiviral drug target for coronaviruses, influenza, and filoviruses
Stuart Weston[SUP] 1 [/SUP], Lauren Baracco[SUP] 1 [/SUP], Chloe Keller[SUP] 1 [/SUP], Krystal Matthews[SUP] 1 [/SUP], Marisa E McGrath[SUP] 1 [/SUP], James Logue[SUP] 1 [/SUP], Janie Liang[SUP] 2 [/SUP], Julie Dyall[SUP] 2 [/SUP], Michael R Holbrook[SUP] 2 [/SUP], Lisa E Hensley[SUP] 2 [/SUP], Peter B Jahrling[SUP] 2 3 [/SUP], Wenbo Yu[SUP] 4 5 [/SUP], Alexander D MacKerell Jr[SUP] 4 5 [/SUP], Matthew B Frieman[SUP] 6 [/SUP]
Affiliations
- PMID: 33184176
- DOI: 10.1073/pnas.2012939117
Abstract
The SARS-CoV-2 pandemic has made it clear that we have a desperate need for antivirals. We present work that the mammalian SKI complex is a broad-spectrum, host-directed, antiviral drug target. Yeast suppressor screening was utilized to find a functional genetic interaction between proteins from influenza A virus (IAV) and Middle East respiratory syndrome coronavirus (MERS-CoV) with eukaryotic proteins that may be potential host factors involved in replication. This screening identified the SKI complex as a potential host factor for both viruses. In mammalian systems siRNA-mediated knockdown of SKI genes inhibited replication of IAV and MERS-CoV. In silico modeling and database screening identified a binding pocket on the SKI complex and compounds predicted to bind. Experimental assays of those compounds identified three chemical structures that were antiviral against IAV and MERS-CoV along with the filoviruses Ebola and Marburg and two further coronaviruses, SARS-CoV and SARS-CoV-2. The mechanism of antiviral activity is through inhibition of viral RNA production. This work defines the mammalian SKI complex as a broad-spectrum antiviral drug target and identifies lead compounds for further development.
Keywords: antiviral host factor; broad-spectrum antiviral; coronavirus; filovirus; influenza.