# Small Molecule Inhibitors of Ebola Virus Polymerase Function

> **NIH NIH R01** · GEORGIA STATE UNIVERSITY · 2021 · $180,913

## Abstract

Project Summary
Filoviruses, which include the ebolaviruses and marburgviruses, are non-segmented, negative-sense RNA
viruses (NNSVs) that cause severe human disease. These viruses are of concern as emerging pathogens and
as potential bioterrorism threats. Their importance and public health impact are reinforced by the West Africa
epidemic that began in winter of 2014 and has resulted in more than 11,000 deaths and the export of Ebola
virus disease to the U.S., the U.K. and Europe. Although the past year has seen progress toward development
of effective vaccines and treatments, current prophylactic and treatment options remain limited. Particularly
lacking are effective small molecule inhibitors. Complicating development of anti-filovirus drugs is the biosafety
level 4 (BSL4) containment needed to work with live filoviruses, which is only available at a few locations
worldwide. With substantial restrictions on the number of investigators who have access to such facilities,
antiviral testing against infectious virus in a high throughput setting is problematic. An alternate approach is to
develop assays of specific viral functions that can be assessed without generation of infectious materials. The
viral RNA-dependent RNA polymerase (RDRP) complex is a particularly promising candidate. The complex
consists of the viral nucleoprotein (NP), viral protein of 35KDa (VP35), VP30 and the large protein (L) which is
the enzymatic component of the complex and the only enzyme encoded by the virus. The RDRP complex is
required for viral mRNA expression and viral genome replication and is therefore essential for virus growth.
Inhibition of the RDRP complex would arrest virus replication. The Basler and Shaw laboratories collaborated
to optimize for 384-well high throughput screening a minigenome assay in which a functional EBOV RDRP
complex is reconstituted by transfection of plasmids that express its four components into mammalian cells.
RDRP activity is measured through the co-expression of a model viral RNA (minigenome RNA) that encodes a
reporter gene flanked by the appropriate virus-derived cis-acting regulatory sequences. This system has been
successfully transferred to collaborator Sumit Chanda at Sanford Burnham Prebys Medical Discovery Institute
where a 6,400 compound pilot screen was performed. This screen yielded hits which were carried through to
BSL4 testing by Robert Davey at Texas Biomedical Research Institute and demonstrated to inhibit Ebola virus
replication. We propose to exploit this assay and this drug discovery pipeline to identify novel small molecule
inhibitors of the Ebola virus polymerase. We will also develop additional HTS-compatible minigenome assays
based on other filoviruses associated with deadly human disease, including Bundibugyo ebolavirus and
Marburg virus, to identify and prioritize hits with pan-filovirus activity. A combination of minigenome assay and
filovirus BSL4 experiments will define mechanisms of action, and togeth...

## Key facts

- **NIH application ID:** 10088374
- **Project number:** 5R01AI125453-05
- **Recipient organization:** GEORGIA STATE UNIVERSITY
- **Principal Investigator:** Christopher F Basler
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $180,913
- **Award type:** 5
- **Project period:** 2017-02-15 → 2021-11-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10088374

## Citation

> US National Institutes of Health, RePORTER application 10088374, Small Molecule Inhibitors of Ebola Virus Polymerase Function (5R01AI125453-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10088374. Licensed CC0.

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