# Fragment-based drug design and substrate envelope model of the Zika virus protease

> **NIH NIH F31** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2021 · $20,452

## Abstract

Project Summary
Zika virus (ZIKV) is a mosquito-borne virus that causes severe neurological diseases such as microcephaly in
neonates and Guillain-Barre syndrome in adults. ZIKV is also a global threat with a large at-risk population in
the tropical and subtropical regions. Furthermore, non-vector borne transmission allows ZIKV to infect people
worldwide. There are neither direct-acting antivirals nor vaccines available against Zika. The ZIKV NS2B-NS3
protease is an attractive therapeutic target because of its essential role in viral maturation. The current
peptidomimetic inhibitors of the ZIKV protease suffer from poor cellular potency and nonselective inhibition of
human proteases. The limitations of these peptidomimetic inhibitors are a result of their peptide scaffold and
covalent warhead groups used to increase their potency. Hence, there is a need to discover clinically viable
protease inhibitors (PIs) to generate lead compounds for further drug development. Fragment-based drug
design (FBDD) is a promising approach for discovering novel scaffolds to overcome the limitations of
peptidomimetics. This project aims to identify clinically viable ZIKV PIs using FBDD. I hypothesize that FBDD
will result in potent and selective ZIKV PIs. Moreover, how the ZIKV protease recognizes diverse substrates
remains unknown. Similar observations of diverse substrates recognition by other viral proteases led to the
discovery of the substrate envelope (SE) model, which states that the conscience volume the diverse
substrates occupy within the active site of a protease is the mode of recognition. I hypothesize that the SE
model can explain diverse substrate recognition by the ZIKV protease. The SE model also explained the
structural basis of drug resistance for those viral proteases. PIs that bind within the consensus volume of the
substrates, i.e. the substrate envelope, are less susceptible to drug resistance. Drug resistance is the biggest
problem facing direct-acting antivirals targeting viral proteases of other highly mutating viruses. Therefore, the
problem of drug resistance must be addressed at the early stages of drug discovery. This proposal allows the
unique opportunity to incorporate the ZIKV SE model into the FBDD approach to preemptively address the
problem of drug resistance. Hence, the ZIKV SE can be a structural tool to guide inhibitor design. To
investigate these hypotheses, I will leverage my expertise in medicinal chemistry and structural biology to
rationally design, synthesize and evaluate the ZIKV PIs. I will rely on my experience in crystallography and
computational biology to solve co-crystal structures of the ZIKV protease with inhibitors and substrates,
respectively. From the protease-substrate complex structures, I will generate a ZIKV protease SE. The results
from this project will provide an understanding of the structural basis of diverse substrate recognition by the
ZIKV protease, and also generate clinically viable PIs for furth...

## Key facts

- **NIH application ID:** 10109012
- **Project number:** 5F31GM131635-03
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Jacqueto Zephyr
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $20,452
- **Award type:** 5
- **Project period:** 2019-02-17 → 2021-09-24

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10109012

## Citation

> US National Institutes of Health, RePORTER application 10109012, Fragment-based drug design and substrate envelope model of the Zika virus protease (5F31GM131635-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10109012. Licensed CC0.

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