# Small molecule-induced degradation of dengue proteins as an antiviral strategy

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2020 · $829,756

## Abstract

PROJECT SUMMARY / ABSTRACT
 Dengue virus (DENV) is a pathogen of high biomedical significance against which we lack effective
countermeasures. Although targeted chemotherapy using combinations of direct-acting antivirals (DAAs) has
proven highly successful against hepatitis C virus infection and HIV, efforts to develop analogous drugs against
DENV have not been successful. The genetic diversity of DENV due to replication by an RNA-dependent RNA
polymerase that lacks proofreading function presents additional challenges by making it difficult to develop
vaccines and antivirals with broad-spectrum coverage of all genotypes within one viral species and facilitating
the rapid development of antiviral resistance when DAAs are used as monotherapies.
 Recently developed methods for small molecule-induced degradation of specific proteins rely on chimeric
molecules (“PROTACs,” “degronimids,” “degraders”) that have a target-specific ligand linked to a moiety that
binds an E3 ubiquitin ligase (e.g., cereblon, VHL). Small molecule-binding leads to ubiquitination and
proteasomal degradation of the target. This results in event-driven rather than occupancy-driven pharmacology
leading to efficient removal of the target from the cell and functional ablation of all of the protein's functions.
Since pharmacological activity does not require constant, stoichiometric engagement of the target, even modest
affinity ligands can be effective degraders. In addition, this mechanism of action can have higher natural barriers
to resistance than conventional inhibitors, as has been demonstrated in the cancer biology field. While these
potential advantages are attractive for antivirals development, it remains unclear the extent to which they can be
leveraged to attain significant antiviral effects. In particular, strong viral expression and localization of viral
processes (and their effectors) on or near specialized membranes may limit the susceptibility of DENV and other
viruses to this pharmacological strategy. Here we propose to explore whether we can successfully deploy
targeted protein degradation against three essential DENV proteins: core, NS4B, and NS5. As there are
currently no approved anti-DENV drugs, there is an urgent need to find new pharmacological strategies to target
this virus. Starting with known inhibitors as targeting ligands for degrader development, we will develop and
validate antiviral degraders. We will then use these as tools to systematically explore potential points of
differentiation between degraders and conventional inhibitors in terms of affinity, potency, selectivity, duration of
action and susceptibility to resistance. We will also optimize validated antiviral degraders to test the efficacy of
this antiviral approach in vivo. The overall goal is to validate degradation of one or more of these targets as an
antiviral strategy with high natural barrier to resistance and to advance first-in-class degraders as leads for the
development of antivir...

## Key facts

- **NIH application ID:** 10052821
- **Project number:** 1R01AI148632-01A1
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** NATHANAEL Schiander GRAY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $829,756
- **Award type:** 1
- **Project period:** 2020-07-23 → 2021-06-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10052821

## Citation

> US National Institutes of Health, RePORTER application 10052821, Small molecule-induced degradation of dengue proteins as an antiviral strategy (1R01AI148632-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10052821. Licensed CC0.

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