# VPS34 inhibitors as SARS-CoV-2 antivirals

> **NIH NIH R21** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $415,889

## Abstract

Summary
SARS-CoV-2, a Betacoronavirus genus, is an enveloped positive-sense, RNA virus responsible
for a current pandemic. Because of its profound impact on society and human health there is an
urgent need to understand SARS-CoV-2 replication requirements and to identify therapeutic
strategies. Repurposing drugs developed for other purposes may provide a shortcut to therapeutic
development. The use of compounds known to target specific host factors may also elucidate key
pathways needed for virus replication. Coronavirus (CoV) replication involves multiple critical
interactions with host cell membranes. One of the most striking features of CoV infection is the
establishment of membrane-associated replication organelles that serve as the main sites of viral
RNA synthesis. The origin of these membrane organelles is incompletely understood. Because
the specific host pathways required for SARS-CoV-2 replication organelle formation are not
defined, we asked whether SARS-CoV-2 is susceptible to modulators of lipid metabolism by
assessing the sensitivity of the virus to VPS34 inhibitors of VPS34, a lipid kinase required for
autophagy and endosomal trafficking; Triacsin C, an inhibitor of long chain fatty acyl CoA
synthetase (ACSL) and Orlistat, an inhibitor of fatty acid synthase (FASN). Our preliminary data
indicate that inhibitors of VPS34 potently inhibited SARS-CoV-2 replication, whereas an FDA-
approved inhibitor of a different class of PI3K had minimal effect on replication. Targeting FASN
and ACSL also impairs SARS-CoV-2 replication. These data suggest that VPS34, ACSL and
FASN play important roles in replication center formation and virus growth and suggest these
enzymes as therapeutic targets. We will test the hypothesis that VPS34, ACSL and FASN are
critical for SARS-Cov-2 infection by evaluating additional small molecule inhibitors of these
enzymes and by measuring SARS-CoV-2 replication in genetic knockdowns or knockouts of these
host enzymes. We will define mechanisms of inhibition and test the hypothesis that generation
of membrane-associated viral replication centers will be disrupted. Finally, we will assess the in
vivo efficacy of VSP34 inhibitor PIK-III and systemically administered Orlistat in SARS-coV-2-
infected hamsters to evaluate the therapeutic potential of inhibitors of lipid metabolism.

## Key facts

- **NIH application ID:** 10534720
- **Project number:** 7R21AI161104-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Christopher F Basler
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $415,889
- **Award type:** 7
- **Project period:** 2021-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10534720

## Citation

> US National Institutes of Health, RePORTER application 10534720, VPS34 inhibitors as SARS-CoV-2 antivirals (7R21AI161104-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10534720. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*