# Development of MS2045 for inhibition of Zika methyltransferase

> **NIH NIH R21** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $211,250

## Abstract

Project Summary
The Zika virus (ZIKV) is a member of the Flavivirus genus that includes other arthropod-borne human pathogens
such as dengue virus and West Nile virus, among others. ZIKV’s link to microcephaly in newborn infants and the
Guillan-Barré syndrome in adults has invigorated measures to develop a vaccine, as well as efforts to develop
antivirals based on targeting enzymatic activities central to the life cycle and survival of ZIKV. One such
enzymatic activity is encoded by the methyltransferase (MTase) domain, located at the N-terminus of the
nonstructural protein NS5. Taking a structure informed approach, we have succeeded in identifying a novel
“lead-like” compound (MS2045) for the inhibition of ZIKV’s NS5 MTase activity and for blocking its replication.
MS2045 provides a basis for further chemistry and the development of even more potent inhibitors. In aim 1,
we will a) design MS2045 analogs with the capacity to establish specific interactions with unique amino acids of
ZIKV MTase as a means to provide additional selectivity against the human RNA 5’-cap MTases; b) chemically
synthesize these analogs and produce them to a purity of 95% for in vitro and cell-based assays, and for
structural studies. In aim 2, we will a) perform biophysical assays to assess the ability of these analogs to
selectively bind the ZIKV NS5-MTase as compared to the human RNA 5’-cap MTases and test their ability to
inhibit RNA methylation; b) test these analogs in viral cell-based assays to assess their efficacy in blocking viral
replication; c) determine structures ZIKV NS5-Mtase with select analogs for additional, iterative rounds of
structure activity relationships (SARs). Collectively, these studies will help to identify analogs of MS2045 that
can be potentially developed into potent and selective inhibitors of NS5-MTase from ZIKV (and other pathogenic
flaviviruses)

## Key facts

- **NIH application ID:** 10758590
- **Project number:** 5R21AI175733-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** ANEEL K. AGGARWAL
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $211,250
- **Award type:** 5
- **Project period:** 2023-01-02 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10758590

## Citation

> US National Institutes of Health, RePORTER application 10758590, Development of MS2045 for inhibition of Zika methyltransferase (5R21AI175733-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10758590. Licensed CC0.

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