# Broad Spectrum Anti-viral Compounds Targeting the SKI Complex

> **NIH NIH R21** · UNIVERSITY OF MARYLAND BALTIMORE · 2021 · $193,125

## Abstract

Project Summary
The RNA Exosome and SKI complex are major cellular machines that degrade host RNA. This
machine is required for several reasons in the cell including maintenance of current RNA levels
and to reduce the level of cytoplasmic RNA such that the RIGI and MDA5 sensors can detect viral
RNA other than host RNA. The SKI complex was identified in a genetic screen as a host protein
that interacts with both Influenza NS1 and MERS-CoV ORF4a. We were able to demonstrate that
knocking down these proteins in cells caused a reduction in viral replication and an increase in
Interferon stimulated gene induction, irrespective of whether a virus was there or not. The SKI
complex in yeast has been crystalized and upon modeling of the human structure, we in silico
identified compounds that could potentially bind to a member of the complex, WDR61. In cell
culture experiments, we identified 4 compounds from the 40 identified in the modeling, that block
Influenza virus, MERS-CoV and SARS-CoV replication. In this proposal, we will determine the
mechanism of action of the compounds and NS1 and ORF4a on the SKI complex. We will also
initiate in vivo studies to evaluate the antiviral effectiveness of the SKI targeted plasmids on
Influenza virus and MERS-CoV mouse models. This work will validate a novel host target and
compounds directed at the SKI complex as broadly acting antivirals.

## Key facts

- **NIH application ID:** 10183158
- **Project number:** 5R21AI153480-02
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Matthew Bryan Frieman
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $193,125
- **Award type:** 5
- **Project period:** 2020-06-05 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10183158

## Citation

> US National Institutes of Health, RePORTER application 10183158, Broad Spectrum Anti-viral Compounds Targeting the SKI Complex (5R21AI153480-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10183158. Licensed CC0.

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