# Aloperine derivatives as novel anti-influenza agents

> **NIH NIH R21** · DUKE UNIVERSITY · 2020 · $201,250

## Abstract

Influenza is a contagious respiratory illness caused by influenza virus, which can cause mild to severe illness,
and at times can lead to death. Currently, the neuraminidase (NA) inhibitors, oseltamivir, zanamivir, and
peramivir, are the FDA-approved anti-Influenza virus drugs recommended by the US CDC for use against
recently circulating influenza viruses. However, there are many different flu virus subtypes and they are constantly
changing. This is further compounded by emerging drug resistance and limited effectiveness associated with
anti-flu drugs. Thus, novel and effective antiviral agents are needed to cope with influenza. The long-term
goal of this study is to identify novel anti-influenza virus agents with potent and broad activity to control flu
virus infection. As a step toward this goal, we have identified a class of quinolizidines, such as aloperine, that
inhibit multiple subtypes of influenza viruses including a CDC panel of NA inhibitor resistant influenza A and B
viruses at sub-uM concentrations. Targeting the viral nucleoprotein (NP) appears to be responsible for the
broad anti-influenza virus activity of the quinolizidines. More importantly, a lead aloperine derivative is effective
in vivo using a mouse model. With these promising results, the goal of this research project is to improve the
potency of the quinolizidines and to elucidate their mechanism of action. The working hypothesis is that
through rational drug design, quinolizidine derivatives with potent and broad anti-influenza virus activity can be
obtained. Two Specific Aims will be carried out to test this hypothesis and achieve our goal in identifying
promising anti-influenza virus agents. Aim 1 is to improve the potency of quinolizidines by structural
modifications. Our approach to achieve this aim is to optimize the functional groups of the quinolizidines to
obtain derivatives with low nM potency and optimal pharmacological profiles. Aim 2 is to establish the antiviral
profiles and to elucidate the mechanism of action of the quinolizidines. The goal of this aim includes
determining the pharmacological profiles and defining mechanisms of action of the quinolizidines.
Pharmacological evaluation will focus on determining the breadth of antiviral activity and the efficacy of
quinolizidine derivatives in a mouse model. The hit compound, aloperine, is a quinolizidine with unique
physicochemical and biological properties suitable for lead optimization. It has been tested in cell and animal
models for its therapeutic effects in ulcerative colitis and regulation of inflammatory cytokines. Our preliminary
lead optimization efforts have resulted in derivatives with sub-uM activity. Completion of the proposed study is
expected to yield new anti-flu agents that inhibit a broad spectrum of influenza viruses, including viral strains
that are resistant to the current CDC recommended anti-influenza therapeutics, at low nM potency.

## Key facts

- **NIH application ID:** 9891004
- **Project number:** 5R21AI139397-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Chin-Ho Chen
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $201,250
- **Award type:** 5
- **Project period:** 2019-03-11 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9891004

## Citation

> US National Institutes of Health, RePORTER application 9891004, Aloperine derivatives as novel anti-influenza agents (5R21AI139397-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9891004. Licensed CC0.

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