# Develop broad-spectrum antiviral agents against COVID-19 based on innate immune response to SARS-CoV-2 infection

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2021 · $380,328

## Abstract

ABSTRACT
The goals of this proposal are to determine the type I interferon (IFN-I)-mediated antiviral gene program
against SARS-CoV-2 infection and to develop novel broad-spectrum antiviral agents (BSAAs) for the treatment
of COVID-19 and other emerging infectious diseases. There are no effective therapeutic agents currently
available in the fight against the global COVID-19 pandemic, in which SARS-CoV-2 has infected millions of
people in confirmed cases and caused hundreds of thousands of fatalities. Drugs that target a single virus, like
the inhibitors of HIV reverse transcriptase and influenza neuraminidase, require a comprehensive
understanding of the lifecycle and disease mechanisms of the virus, which makes development of these drugs
necessarily time-consuming. Outbreaks of infection caused by novel emerging highly pathogenic viruses,
including avian influenza, SARS, Ebola, Zika virus (ZIKV) and SARS-CoV-2, have become a major concern in
the past two decades. We cannot rely on the traditional virus-specific drugs to treat diseases caused by these
unpredictable emerging viruses. Therefore, it is extremely important to develop BSAAs effective against a
range of viruses. My laboratory has been studying anti-viral innate immune responses, particularly the IFN-I
signaling pathway and its downstream gene program, for the last 20 years. While the field has previously
focused only on interferon-stimulated genes (ISGs), we have demonstrated that ISGs like cholesterol 25-
hydroxylase (CH25H) and IFN-I downregulated genes like fatty acid synthase (FASN) both play important roles
in limiting viral infection and replication. We have also identified multiple small molecules for use as BSAAs,
including 25-hydroxycholersterol (25HC), the metabolic product of CH25H, and the FASN inhibitor C75. In
addition, we have extensively studied host innate immune responses to coronaviral infection: we have
published multiple papers that explain how the host IFN-I signal transduction pathway is activated in response
to infection by coronaviruses like murine hepatitis virus (MHV) and how coronaviruses can suppress their
host’s innate immune responses through the viral papain-like protease (PLpro). Most importantly, in our
preliminary studies we found that 25HC and C75 both have strong inhibitory effects against SARS-CoV-2
infection. We hypothesize that the IFN-I-mediated antiviral gene program involves not only upregulation of
antiviral ISGs but also downregulation of the host genes required for viral infection and replication. We further
hypothesize that by identifying the IFN-I-mediated antiviral gene program against SARS-CoV-2, we will be able
to develop novel antiviral agents to combat COVID-19 and other emerging threats. In this proposal, we will first
determine the IFN-I gene program in innate immune response to SARS-CoV-2. We will also develop 25HC,
25HC analogs and FASN inhibitors as novel antiviral agents against SARS-CoV-2. We believe our studies will
not only...

## Key facts

- **NIH application ID:** 10222540
- **Project number:** 5R01AI158154-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** GENHONG CHENG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $380,328
- **Award type:** 5
- **Project period:** 2020-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10222540

## Citation

> US National Institutes of Health, RePORTER application 10222540, Develop broad-spectrum antiviral agents against COVID-19 based on innate immune response to SARS-CoV-2 infection (5R01AI158154-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10222540. Licensed CC0.

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