# Development of novel antivirals against mpox (monkeypox) virus

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2024 · $783,602

## Abstract

A. Project Summary / Abstract
The ongoing monkeypox (mpox) outbreak, with a total of more than 87,000 cases reported in over 100 non-
endemic countries, highlights the pandemic potential of poxviruses. Due to its zoonotic nature with broad hosts
and unidentified natural reservoirs of the causative agent, mpox virus (MPXV), future spillovers and outbreaks
are expected even if the current outbreak is contained. Although typically manifesting in milder symptoms than
smallpox, MPXV infections can still cause significant morbidity and mortality (up to 10% for clade I) that need to
be therapeutically mitigated. The clinical efficacy of FDA-approved smallpox antiviral drugs is unclear or
unpromising for treating MPXV, necessitating dedicated and expanded efforts in developing MPXV antivirals.
The goal of this grant application is to develop novel antivirals for treating MPXV. Prior research from our team
has developed and validated an efficient and robust reporter assay using the vaccinia virus (VACV), and
identified and characterized three high quality and chemically distinct antiviral hits with strong potencies (EC50 =
0.14‒2.1 M; plaque reduction at 10 M 1,400‒160,000-fold), no cytotoxicity (CC50 > 250 M) and largely
favorable ADME properties. The immediate focus of this grant is to further develop these three hit series into
pre-clinical candidates using a highly integrated, multi-disciplinary approach combining medicinal chemistry,
virology, ADME / pharmacokinetic (PK), toxicity, animal efficacy and proteomics. Three Specific Aims are
proposed: 1) optimization and expansion of the identified hits. Iterative structure-activity relationship (SAR) and
structure-property relationship (SPR) studies will be carried out via extensive analog synthesis, antiviral assay
and ADME profiling to obtain optimized leads. Hit expansion will also be conducted by screening the high quality
synthetic compounds in PI’s lab as well as preselected commercial compounds; Aim 2) in vivo PK, toxicity and
efficacy studies, where the acute and sub-acute toxicity and PK studies in mice will guide compound selection
for efficacy studies in mice; Aim 3) determine the antiviral mechanism of action (MOA). The molecular targets
and antiviral MOA of optimized leads will be determined using a few different methods: a) identify the viral
replication stage(s) targeted by the leads; b) select resistant mutants by passaging virus in cultured cells in the
presence of individual lead compound, and sequence viral genomes to identify affected genes; The compound
will then be tested in recombinant viruses harboring the selected mutations; c) design and synthesize chemical
probes to label, pull down, and identify the target protein(s); d) test metal chelating analogs in resolvase
biochemical assays. Overall, 2-3 antiviral leads with strong potency, favorable PK profiles, minimal toxicities,
and established MOA will be developed, setting the stage for further pre-clinical development of MPXV ...

## Key facts

- **NIH application ID:** 10902932
- **Project number:** 1R01AI183580-01
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Zhengqiang Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $783,602
- **Award type:** 1
- **Project period:** 2024-06-14 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10902932

## Citation

> US National Institutes of Health, RePORTER application 10902932, Development of novel antivirals against mpox (monkeypox) virus (1R01AI183580-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10902932. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*