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SKI complex: A broad-spectrum, host-directed antiviral drug for viruses Including Coronaviruses

As a possible target for broad-spectrum antiviral drugs, the SKI complex, a protein complex involved in different RNA metabolism pathways, has been identified. Already, chemicals that communicate with the SKI complex have been identified. Encouragingly, these chemicals have been shown to inhibit mammalian cell culture replication of coronaviruses, influenza viruses, and filoviruses.

Originally, the SKI complex was described in yeast, but it is also present in mammals. A recent quest for broad-spectrum, host-directed, antiviral targets included both these SKI contexts. The research started with yeast suppressor screening, performed by scientists at the University of Maryland School of Medicine (UMSOM), with the goal of finding a functional genetic interaction between viral proteins and eukaryotic proteins.

This study was publish in Proceedings of the National Academy of Sciences (PNAS), under title "The SKI complex is a broad-spectrum, host-directed antiviral drug target for coronaviruses, influenza, and filoviruses"

Influenza A virus (IAV) and Middle East respiratory syndrome coronavirus (MERS-CoV) screens were performed. Those theoretically involved in promoting viral replication and survival were the eukaryotic proteins of interest. The screens indicated that both viruses required SKI.

Next, UMSOM scientists conducted experiments in mammalian systems and determined that siRNA-mediated SKI gene knockdown prevented IAV and MERS-CoV replication. The UMSOM scientists were inspired by this finding to consider how possible antiviral agents could target the SKI complex.

A binding pocket on the SKI complex and compounds predicted to bind are recognised in silico modelling and database screening, wrote the authors of the paper. "Three chemical structures that were antiviral against IAV and MERS-CoV along with the filoviruses Ebola and Marburg and two additional coronaviruses, SARS-CoV and SARS-CoV-2, were detected by experimental assays of these compounds."

The antiviral activity of the chemicals, the authors proposed, happens through inhibition of the development of viral RNA.

Matthew Frieman, PhD, the study's corresponding author and associate professor of microbiology and immunology at UMSOM, said We have found that disrupting the SKI complex prevents the virus from copying itself which effectively kills it. Compounds targeting the SKI complex have also been reported, not only inhibiting coronaviruses, but also influenza viruses and filoviruses, such as the one that causes Ebola.

Computer modelling was used by Frieman and his colleagues from the Computer-Aided Drug Design Center of the School of Pharmacy and the Center for Biomolecular Therapeutics at UMSOM to identify a binding site on the SKI complex and identify chemical compounds that might bind to this site. These compounds were shown to have antiviral activity against coronaviruses, influenza viruses, and filoviruses (such as Ebola) in subsequent laboratory research. This study also included researchers from the National Institute of Allergy and Infectious Diseases.

The study was sponsored by Gaithersburg, MD-based Emergent BioSolutions, a biopharmaceutical business.

These results are a significant first step in discovering possible new antivirals that could be used to treat a wide variety of deadly infectious diseases, said Stuart Weston, PhD, lead author of the study and a UMSOM research fellow. These medicines have the ability to cure possible pandemic-associated infectious diseases. The next steps include conducting animal experiments to learn more about the safety and effectiveness of these non-FDA approved experimental compounds.

At this point, our compounds exhibiting large antiviral activity are only designed to interact with the SKI complex, the authors of the article noted. We find that the loss of the SKI complex through siRNA targeting eliminates [one of our compounds'] antiviral activity, indicating a need for the complex to generate the antiviral activity observed. The goal of future work is to further examine whether the compounds bind directly to the SKI complex using structural biology methods and to investigate whether other SKI complex functions are affected.

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