# Mechanistic understanding and inhibition of Zika NS5 protein

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA RIVERSIDE · 2020 · $57,686

## Abstract

Mechanistic understanding and inhibition of Zika NS5 and SARS-CoV-2 RdRP proteins
ABSTRACT
 Zika virus (ZIKV) and Coronavirus (CoV) are single-stranded RNA viruses that pose grave threat to public
health. In the first two decades of the 21st century, the global community has already witnessed one outbreak
of Flavivirus, Zika virus (ZIKV), and three zoonotic outbreaks of CoV– severe acute respiratory syndrome
(SARS)-associated coronavirus (SARS-CoV) in 2002, the Middle East respiratory syndrome (MERS)-CoV in
2012, and the most recent, the novel SARS-CoV-2. These viruses are highly transmissible, greatly impacting
the social, societal and economic dynamics. However, there are currently no approved drugs for either ZIKV or
for zoonotic CoV, raising an urgent need for development of novel therapeutic strategies against ZIKV and
CoV infection. This application seeks to develop an antiviral strategy targeting the viral core replication
machinery, RNA-dependent RNA polymerase (RdRP), non-structural protein 5 (NS5) of ZIKV and non-
structural protein 12 (NSP12) of SARS-CoV-2. On one hand, the currently identified small molecule inhibitors
will be evaluated for their efficiency on ZIKV or SARS-CoV-2 inhibition. On the other hand, mechanistic details
of ZIKV NS5 and SARS-CoV-2 RdRP-mediated RNA replication will be investigated, thereby providing a basis
for development of synergistic inhibition strategies targeting various enzymatic steps of ZIKV NS5 and SARS-
CoV-2. In Aim 1, structural, biochemical and cellular approaches will be taken to evaluate the inhibition of ZIKV
NS5- or SARS-CoV-2 RdRP-mediated de novo RNA synthesis by candidate inhibitors. Through evaluation of
the inhibitory effects of the candidate inhibitors on ZIKV NS5 or SARS-CoV-2 RdRP, this application will
address whether these compounds can serve as inhibitors to ZIKV NS5 or SARS-CoV-2, and more importantly,
to provide a basis for structure-based drug optimization for ZIKV NS5 or SARS-CoV-2. In Aim 2, the
mechanistic basis of ZIKV NS5 and SARS-CoV-2 RdRP-mediated RNA replication will be determined through
structure elucidation of the replication complexes of ZIKV NS5 or SARS-CoV-2 RdRP, combined with
enzymatic analyses. The structural knowledge on the replication complexes of ZIKV NS5 and SARS-CoV-2
RdRP will then provide a framework for structure-based drug design for comprehensive inhibition of ZIKV NS5
and SARS-CoV-2 infection. Together, the proposed studies will provide key mechanistic insights into the viral
RdRP-mediated genome replication and establish a foundation for development of effective inhibitors against
ZIKV and SARS-CoV-2.

## Key facts

- **NIH application ID:** 10126603
- **Project number:** 3R21AI147057-01S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA RIVERSIDE
- **Principal Investigator:** Rong Hai
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $57,686
- **Award type:** 3
- **Project period:** 2020-05-11 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10126603

## Citation

> US National Institutes of Health, RePORTER application 10126603, Mechanistic understanding and inhibition of Zika NS5 protein (3R21AI147057-01S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10126603. Licensed CC0.

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