# Establishing the Therapeutic Efficacy of Alpha-1-Antitrypsin and Enoxaparin Against COVID-19

> **NIH VA I01** · VA EASTERN COLORADO HEALTH CARE SYSTEM · 2024 · —

## Abstract

The clinical outcome for patients with severe COVID-19 remains poor due to the lack of highly efficacious
treatment for such individuals. Finding a better remedy for them is an important niche and immediate unmet
need. The aim of this pre-clinical project is to substantiate the therapeutic effect of combined alpha-1-
antitrypsin (AAT) + enoxaparin (a low molecular weight heparin) against SARS-CoV-2 infection and its
consequences. Establishing the efficacy of AAT + enoxaparin combination will provide a necessary foundation
for future clinical trials with the goal of employing effective therapy for those with severe COVID-19.
 We have novel biological evidence supported by Artificial Intelligence-based molecular modeling
that enoxaparin synergizes with AAT to inhibit TMPRSS2 (a cell surface protease that activates the spike
protein of SARS-CoV-2) and to reduce SARS-CoV-2 burden in primary human airway epithelial cells (hAEc)
and monocyte-derived macrophages (MDM). Because both AAT and enoxaparin embrace a panoply of
activities that antagonize other pathogenic mechanisms of severe COVID-19 – including anti-inflammatory,
anti-thrombotic, pro-autophagy (known to kill MERS-CoV), and endothelial cell protection – we hypothesize
that the AAT + enoxaparin combination will be most effective (compared to each alone) in mitigating SARS-
CoV-2 infection and its consequences.
 We will use three complementary models to elucidate the efficacy of AAT, enoxaparin, and combination of
both against SARS-CoV-2 infection: (i) primary hAEc since they express high ACE2 levels, fulminant airway
disease occurs, and infection of ciliated hAEc and breach of their defense initiates a portal of entry into the
lower airways / alveoli to cause COVID-19 pneumonia; (ii) MDM + plasma derived from AAT-deficient
individuals immediately before and immediately after receiving routine intravenous AAT since macrophages
are key orchestrators of the hyper-inflammatory response seen with COVID-19; and (iii) two murine models,
one with wildtype AAT and another with AAT knocked out.
Aim 1: Determine in primary hAEc the mechanisms by which AAT, enoxaparin, and both reduce SARS-
CoV-2 infection and its consequences. Approach: hAEc will be infected with SARS-CoV-2 followed by no
treatment or treatment with AAT, enoxaparin, or combination of both and assayed for viral load, autophagic
flux, pro-inflammatory cytokines, and hAEc viability and barrier integrity.
Aim 2: Determine in macrophages the mechanisms by which AAT (given in vivo) ± enoxaparin mitigate
SARS-CoV-2 infection. Approach: infect human MDM cultured in autologous plasma – prepared from AAT-
deficient individuals before and after AAT infusions ± ex vivo enoxaparin – with SARS-CoV-2 and determine
viral load, autophagic flux, and pro-inflammatory cytokine / macrophage extracellular trap (METs) production.
Aim 3: Determine if SARS-CoV-2 infection of mice is mitigated by AAT, enoxaparin, and combination of
both. Approach: transgenic (Tg) ...

## Key facts

- **NIH application ID:** 10869869
- **Project number:** 5I01BX005651-02
- **Recipient organization:** VA EASTERN COLORADO HEALTH CARE SYSTEM
- **Principal Investigator:** EDWARD D CHAN
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2023-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10869869

## Citation

> US National Institutes of Health, RePORTER application 10869869, Establishing the Therapeutic Efficacy of Alpha-1-Antitrypsin and Enoxaparin Against COVID-19 (5I01BX005651-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10869869. Licensed CC0.

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