# Preclinical studies to establish the combination of apoA-I mimetic peptides and statins as novel therapy for COVID-19

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2021 · $335,400

## Abstract

PROJECT SUMMARY/ABSTRACT
The SARS-CoV-2 pandemic emphasizes the urgent need to determine pathways that can be targeted by novel
antivirals. This proposal describes the use of the combination of apoA-I mimetics with statins as novel therapy
for COVID-19. SARS-CoV-2 utilizes mitochondria to replicate in lung epithelial cells. Mitochondrial reactive
oxygen species (mito-ROS) induce alterations of lipids, membranes and redox sensitive proteins and ultimately
viral replication. Thus, we hypothesized that the antioxidant ApoA-I mimetic peptide 4F, that targets lipids,
mito-ROS and redox pathways, has antiviral activity against SARS-CoV-2. We confirmed that 4F not only has
antiviral activity against SARS-CoV-2 but also has anti-inflammatory effects in epithelial cells that may alleviate
lung injury in COVID-19. Importantly, prior studies have shown that 4F and statins may have major additive in
vivo effects on altered lipids, oxidative stress and inflammation that are instigators of cardiovascular disease.
Human studies suggest that statin use was associated with a lower risk of developing severe COVID-19. Both
statins and 4F attenuate activation of the Toll like Receptor (TLR)-CD147-NF-κB pathways, which are key
inflammatory pathways in coronavirus infections. We hypothesize that the combination of 4F and statins has
antiviral activity against SARS-CoV-2 in lung epithelial cells and anti-inflammatory activity in lung epithelial
cells, macrophages and vascular endothelial cells by attenuating the redox sensitive TLR-CD147-NF-κB
proviral and proinflammatory pathway. Thus, in Aim 1 of this proposal and using an air-liquid interface (ALI)
culture of primary airway epithelial cells, and cell lines in combination with viral and immune assays, we will
determine the mechanisms how the combination of 4F with atorvastatin attenuates aberrant activation of the
TLR-CD147-NF-κB pathway as a novel mechanism that drives viral replication and associated inflammatory
responses in SARS-CoV-2 infected lung cells. Given that vascular dysfunction is a possible mechanism of
chronic post-infectious sequalae of COVID-19, in Aim 2 of this proposal and using an established ex vivo
model of atherogenesis and vascular dysfunction and peripheral blood mononuclear cells (PBMCs) from
COVID-19 patients in combination with immune assays, we will determine whether 4F and atorvastatin
attenuate aberrant activation of the TLR-CD147-NF-κB pathway in macrophages from COVID-19 patients that
interact ex vivo with endothelial cells to drive proinflammatory proatherogenic responses. Our independent
aims will complement each other and will advance the use of the combination of apoA-I mimetic peptides and
statins as novel therapy for COVID-19. This work is innovative, interdisciplinary, public health-oriented, and
directly addresses the goals of funding opportunity.

## Key facts

- **NIH application ID:** 10456506
- **Project number:** 3R01AG059502-04S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Theodoros Kelesidis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $335,400
- **Award type:** 3
- **Project period:** 2018-09-30 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10456506

## Citation

> US National Institutes of Health, RePORTER application 10456506, Preclinical studies to establish the combination of apoA-I mimetic peptides and statins as novel therapy for COVID-19 (3R01AG059502-04S1). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/10456506. Licensed CC0.

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