# Inhibitors of SARS-CoV-2 Polymerase

> **NIH NIH U19** · SCRIPPS RESEARCH INSTITUTE, THE · 2022 · $1,458,931

## Abstract

SUMMARY
The SARS-CoV-2 RNA-dependent RNA polymerase (RDRP), non-structural protein 12 (NSP12), which in
complex with viral proteins nsp7 and nsp8 carries out essential RNA synthesis reactions, is an attractive and
well-validated target for antivirals. To date, nucleoside analogs that inhibit RDRP activity show promise as
COVID-19 treatments. Among these is remdesivir (RDV), a prodrug of the adenosine analog GS-441524 and the
first FDA-approved antiviral for the treatment of COVID-19. Recent phase 3 clinical data for molnupiravir, a
prodrug of β-D-N4-hydroxycytidine (NHC), has encouraged Merck to seek Emergency Authorization Use.
Whereas RDV suffers from lack of oral bioavailability, limiting its outpatient use, molnupiravir is orally
administered but requires frequent high doses. Further, none of the most advanced nucleoside inhibitors were
developed specifically to treat coronavirus infections. Here, we propose three parallel approaches to provide
novel drugs optimized to target the SARS-CoV-2 RDRP and treat coronavirus infections. In the first approach,
we build on promising preliminary data in non-human primates as we aim to develop a prodrug with improved
oral exposure vs. RDV so as to enable oral administration for use in the outpatient setting, preferably a once a
day dosing regimen. Our second approach seeks to identify and optimize novel nucleoside analogs against
SARS-CoV-2 RDRP. Key to this approach will be the screening of a nucleoside library that includes 167 novel
analogs for activity against SARS-CoV-2 in human bronchial epithelial cells differentiated in an air-liquid
interface. Third, we will use a cell-based assay of SARS-CoV-2 RDRP to screen a novel library of structurally
diverse “fully functionalized fragments” and a second library of cysteine- and lysine-reactive compounds to
identify allosteric inhibitors. Promising RDRP inhibitors will be tested for pan-coronavirus potential by testing
against SARS-CoV, MERS-CoV and seasonal coronaviruses. Because RDRPs share conserved structures,
broad-spectrum activity is possible and would be desirable. Therefore, we will evaluate top RDRP inhibitors from
this Project and from Projects 5 and 6, which will focus on arboviruses and hemorrhagic fever viruses, in
established biochemical RDRP assays for a panel of emerging viruses. These assays will provide mechanistic
insight into the basis for broad-spectrum activity. In parallel, deep-sequencing approaches will be used to define
MOA in infected cells and animals. For these studies, compound progression will be driven by iterative
optimization by the Medicinal Chemistry Core (Core B), biological profiling against coronavirus replication assays
in the HTS Core (Core A), ADME, PK and toxicology profiling from the Pharmacology Core (Core C), animal
efficacy studies in collaboration with the Organoid and Animal Model Core (Core D), and structure-based drug
discovery with the Structural and Modeling Core (Core E) to deliver a pan-active coronav...

## Key facts

- **NIH application ID:** 10514325
- **Project number:** 1U19AI171443-01
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Christopher F Basler
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,458,931
- **Award type:** 1
- **Project period:** 2022-05-16 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10514325

## Citation

> US National Institutes of Health, RePORTER application 10514325, Inhibitors of SARS-CoV-2 Polymerase (1U19AI171443-01). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10514325. Licensed CC0.

---

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