# Broad-spectrum antiviral activity of antisense oligonucleotides targeting GBF1 against SARS-CoV-2 and influenza viruses

## TL;DR

Researchers found that targeting a human protein called GBF1 with a new type of drug can stop both SARS-CoV-2 and influenza viruses from spreading in cells.

## Contribution

A new broad-spectrum antiviral strategy using antisense oligonucleotides targeting GBF1 is proposed.

## Key findings

- GBF1 is essential for replication of influenza, SARS-CoV-2, and HCoV-229E.
- GBF1-ASO#1502 inhibits these viruses in vitro with nanomolar IC50 values.
- GBF1 relocates to viral replication sites during SARS-CoV-2 infection.

## Abstract

Influenza viruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are respiratory pathogens that continue to challenge global health due to their efficient transmission and ability to circumvent virus-specific treatments. Targeting host factors that are essential for viral replication may enable the development of broad-spectrum antivirals with reduced resistance potential. Here, we used small interfering RNA (siRNA) to screen 91 host factors previously implicated in influenza virus replication and identified seven that were also required for SARS-CoV-2 replication. Of these, Golgi-specific brefeldin A-resistance factor 1 (GBF1), a guanine nucleotide exchange factor involved in coat protein complex I (COPI) vesicle trafficking, was also involved in human coronavirus 229E replication. We found that GBF1 relocated to sites of viral replication in SARS-CoV-2-infected cells. Using a computational design pipeline, we generated antisense oligonucleotides (ASOs) targeting GBF1. The lead candidate, GBF1-ASO#1502, potently inhibited influenza viruses and SARS-CoV-2 in vitro, with nanomolar half-maximal inhibitory concentration (IC50) values and favorable selectivity indices. GBF1-targeting ASOs thus represent a promising host-directed antiviral approach for controlling respiratory RNA viruses.

•GBF1 is a host factor for influenza, SARS-CoV-2, and HCoV-229E replication•GBF1 knockdown suppresses SARS-CoV-2 viral growth and subgenomic mRNAs•GBF1 relocates to viral replication sites during SARS-CoV-2 infection•GBF1-targeting ASOs represent a potential host-directed antiviral strategy

GBF1 is a host factor for influenza, SARS-CoV-2, and HCoV-229E replication

GBF1 knockdown suppresses SARS-CoV-2 viral growth and subgenomic mRNAs

GBF1 relocates to viral replication sites during SARS-CoV-2 infection

GBF1-targeting ASOs represent a potential host-directed antiviral strategy

Nucleic acids; Virology; Viral microbiology