# Discovery of broad-spectrum influenza antivirals with a high genetic barrier to drug resistance by targeting the viral polymerase

> **NIH NIH R21** · UNIVERSITY OF ARIZONA · 2020 · $194,099

## Abstract

Project Summary
 Despite the existence of vaccines and antiviral drugs, global annual death tolls attributed to influenza virus
infection are ~500,000. Currently there is only one orally bioavailable drug, oseltamivir, that is still in use to
treat influenza infection. The alarming fact is that oseltamivir-resistant influenza strains have already been
isolated from human patients, and several of them appear to have adapted the fitness of transmission.
Thus there is a pressing need to develop novel antivirals to combat these drug-resistant influenza viruses.
They can be used either alone to inhibit oseltamivir-resistant strains or in combination with oseltamivir to
decrease the pace of drug resistance evolution. Moreover, as the influenza viruses circulating among
humans consist of at least two influenza A strains (H1N1 and H3N2) and two B strains (Yamagata and
Victoria), it is also desirable to have one antiviral drug with broad-spectrum antiviral activity against all four
strains.
 In response to the need for a next generation of antiviral drugs with broad-spectrum antiviral
activity, especially against multidrug-resistant influenza viruses, we performed an in silico screening of an
in-house library of small molecules predominantly prepared by one-pot multicomponent reaction
(MCR) methodologies against the virus polymerase PA subunit and have identified several promising hits. One
compound, UAWJ85, inhibits several multidrug-resistant influenza A and B viruses with EC50 values range
from single to sub-micromolar. This compound also displays a high in vitro genetic barrier to drug
resistance, as no resistant viruses were selected after 10 passages with increasing concentrations of the
compound. Mechanistic studies confirmed the inhibition of polymerase PA-PB1 subunit interactions by
UAWJ85. The broad-spectrum antiviral activity and high in vitro genetic barrier to drug resistance of
UAWJ85, coupled with the expeditious structure–activity relationship studies using the one-pot Ugi-
Azide 4CR methodology, have led us to further optimize the antiviral potency, selectivity index, in vitro and in
vivo PK properties of lead compounds and test their in vivo antiviral efficacy in mice.
 In Aim 1, we will optimize the in vitro antiviral and pharmacokinetic properties of UAWJ85. A list
of criteria was imposed for compound progression. The goal is to prioritize lead compounds for in vivo
mice studies. In Aim 2, we will will test the in vivo PK and antiviral activity of UAWJ85 or its analogs using
the influenza virus infected mice model.
 In summary, the advantage of exploring MCR products for broad-spectrum anti-influenza drugs has been
clearly demonstrated by the preliminary results. This proposal, if successfully implemented, will lead to the
urgently needed antivirals to combat both seasonal outbreaks and the next influenza pandemic.

## Key facts

- **NIH application ID:** 9882204
- **Project number:** 5R21AI144887-02
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Jun Wang
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $194,099
- **Award type:** 5
- **Project period:** 2019-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9882204

## Citation

> US National Institutes of Health, RePORTER application 9882204, Discovery of broad-spectrum influenza antivirals with a high genetic barrier to drug resistance by targeting the viral polymerase (5R21AI144887-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9882204. Licensed CC0.

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