# Mechanistic understanding and inhibition of Zika NS5 protein

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA RIVERSIDE · 2020 · $233,250

## Abstract

Mechanistic understanding and inhibition of Zika NS5 protein
ABSTRACT
 Zika virus (ZIKV) belongs to the single-stranded RNA-containing flavivirus family. Its recent outbreak and
implication in human diseases (e.g. neurological disorders) have raised a global health alarm, and urgency to
develop a therapeutic strategy against ZIKV infection. However, there are no currently approved antivirals
against ZIKV available yet. This application seeks to develop an antiviral strategy against the non-structural
protein 5 (NS5) of ZIKV, which is responsible for virus-specific genomic replication. On one hand, the currently
identified flavivirus inhibitors will be evaluated for their efficiency on ZIKV inhibition. On the other hand,
mechanistic details of ZIKV NS5-mediated RNA replication will be investigated, thereby providing a basis for
development of synergistic inhibition strategies targeting various enzymatic steps of ZIKV NS5. In Aim 1,
structural, biochemical and cellular approaches will be taken to evaluate the inhibition of ZIKV NS5-mediated
de novo RNA synthesis by the thiophenyl propargyl alcohol (TPA) compounds, the non-nucleoside inhibitors
(NNIs) that have been identified as inhibitors for Dengue virus (DENV) NS5, in vitro and ex vivo. Our recent
structural study of ZIKV NS5 revealed that the TPA-binding site of DENV NS5 is conserved in ZIKV NS5.
Through evaluation of the inhibitory effects of the TPA compounds on ZIKV NS5, this application will address
whether the TPA compounds can serve as inhibitors to ZIKV NS5, and more importantly, to provide a basis for
structure-based drug optimization for ZIKV NS5. In Aim 2, the mechanistic basis of ZIKV NS5-mediated RNA
replication will be determined through structure elucidation of the replication initiation and elongation
complexes of ZIKV NS5, combined with mutational and enzymatic analyses. The structural knowledge on the
conformational transition of ZIKV NS5 from replication initiation to elongation will then provide a framework for
structure-based drug design for comprehensive inhibition of ZIKV NS5 activity. Together, the proposed studies
will provide key mechanistic insights into the NS5-mediated genome replication and establish a foundation for
development of effective inhibitors against ZIKV.

## Key facts

- **NIH application ID:** 9964663
- **Project number:** 5R21AI147057-02
- **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:** $233,250
- **Award type:** 5
- **Project period:** 2019-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9964663

## Citation

> US National Institutes of Health, RePORTER application 9964663, Mechanistic understanding and inhibition of Zika NS5 protein (5R21AI147057-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9964663. Licensed CC0.

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