# Targeting a Human Acyltransferase for Broad-Spectrum Antivirals

> **NIH NIH R21** · BELLBROOK LABS, LLC · 2021 · $390,500

## Abstract

Abstract
SARS CoV-2 and related coronaviruses hijack host proteins to facilitate cell entry, replication and
immune suppression. Targeting hijacked host proteins is an attractive strategy for development
of broad-spectrum antiviral drugs because the same proteins are often targeted by multiple
viruses. A global SARS-CoV-2/human protein/protein interaction analysis recently revealed one
such target: the human acyltransferase DHHC5, which catalyzes palmitoylation of proteins to
regulate trafficking in the endocytic pathway, was shown to interact with the SARS-CoV-2 Spike
protein. This finding was exciting in itself, but in light of multiple lines of evidence indicating that
DHHC5’s role in localizing proteins at the plasma membrane is hijacked by diverse pathogens to
gain entry into the cell, it is compelling rationale for developing DHHC5 inhibitors to test as
antivirals.
We propose to develop selective DHHC5 inhibitors as lead molecules to test in animal models of
coronavirus infection. Currently, the tools for a small molecule drug discovery effort for this target
are lacking: there is very little structural information on DHHC family members and no robust HTS
assays. The goals of this R21 proposal are to develop and validate the tools needed for discovery
of DHHC5 inhibitors and initiate a lead discovery program. To address this, we will develop and
validate a robust, quantitative high throughput DHHC5 enzymatic assay based on a coupled
fluorescence polarization immunoassay (FPIA) that will serve as a critical tool for screening and
performing hit-to-lead/SAR studies. We will use the assay to screen a diversity library, validate
the hits and prioritize them based on physicochemical properties, potency, selectivity, mechanism
of action and functional activity. Additionally, we will produce a cocrystal structure of DHHC5 in
complex with a validated hit molecule. Completion of these aims will establish technical feasibility
for pursuing a structure-driven design approach to discover lead molecules targeting DHHC5,
which could ultimately result in the development of antivirals with broad spectrum activity against
SARS-CoV-2 and coronavirus pathogens that emerge in the future.

## Key facts

- **NIH application ID:** 10223496
- **Project number:** 1R21AI160508-01
- **Recipient organization:** BELLBROOK LABS, LLC
- **Principal Investigator:** Robert G Lowery
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $390,500
- **Award type:** 1
- **Project period:** 2021-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10223496

## Citation

> US National Institutes of Health, RePORTER application 10223496, Targeting a Human Acyltransferase for Broad-Spectrum Antivirals (1R21AI160508-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10223496. Licensed CC0.

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