# Structure guided discovery of chemical probes for targeting Zika methyltransferase

> **NIH NIH R21** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $211,875

## Abstract

The Flavivirus genus includes mosquito-borne human pathogens, such as dengue virus, yellow fever virus,
and the Zika virus (ZIKV), among others. ZIKV's recent spread in Americas and its link to microcephaly in
newborn infants and the Guillan-Barré syndrome in adults has invigorated efforts to develop a vaccine, as well
as measures to eradicate the Aedes mosquito vectors. In addition to these measures, it is equally important 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. As a step towards this goal, we have determined several high-resolution crystal
structures of the ZIKV NS5-MTase. Together, these structures (all determined to better than 1.5 Å in
resolution) provide a powerful new framework for the design and synthesis of small molecules that selectively
target MTase from ZIKV and other pathogenic flaviviruses. In aim 1, we will a) use the structural information to
design S-adenosylmethionine (SAM) based analogs with the capacity to interact with unique amino acids in
ZIKV MTase, and which extend deeper into the RNA binding tunnel to block RNA binding. We will also design
analogs with substituents on both the adenine base and the methionine portion of SAM to provide additional
selectivity against the human RNA 5'-cap MTases. We will b) chemically synthesize the analogs and produce
them to a purity of 95% for in vitro and cell-based assays, as well as for cocrystallization with the ZIKV NS5-
MTase. 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). Together, the proposed studies will help to identify new small molecules that can be
potentially developed into inhibitors of ZIKV NS5-MTase.

## Key facts

- **NIH application ID:** 9821735
- **Project number:** 5R21AI142337-02
- **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:** 2020
- **Award amount:** $211,875
- **Award type:** 5
- **Project period:** 2018-11-12 → 2020-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9821735

## Citation

> US National Institutes of Health, RePORTER application 9821735, Structure guided discovery of chemical probes for targeting Zika methyltransferase (5R21AI142337-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9821735. Licensed CC0.

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