Alpha-1 Antitrypsin for COVID-19 Treatment: Dual Role in Antiviral Infection and Anti-Inflammation

Abstract

Many drugs have been approved for clinical trials for the treatment of COVID-19 disease, focusing on either antiviral or anti-inflammatory approaches. Combining antiviral and anti-inflammatory drugs or therapies together may be more effective. Human alpha-1 antitrypsin (A1AT) is a blood circulating glycoprotein that is best known as a protease inhibitor. It has been used to treat emphysema patients with A1AT deficiency for decades. We and others have demonstrated its role in reducing acute lung injury by inhibiting inflammation, cell death, coagulation, and neutrophil elastase activation. Recently, A1AT has been found to inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by inhibiting transmembrane serine protease 2 (TMPRSS2), a protease involved in the entry of SARS-CoV-2 into host cells. This dual role of both antiviral infection and anti-inflammation makes A1AT a unique and excellent candidate for COVID-19 treatment. Three clinical trials of A1AT for COVID-19 treatment have recently been approved in several countries. It is important to determine whether A1AT can prevent the progress from moderate to severe lung injury and eventually to be used to treat COVID-19 patients with acute respiratory distress syndrome.

Neutrophil Elastase and Proteinase 3 Cleavage Sites Are Adjacent to the Polybasic Sequence within the Proteolytic Sensitive Activation Loop of the SARS-CoV-2 Spike Protein

“…Thus, protease inhibitors, such as alpha-1-antitrypsin, which inhibits TMPRSS2, NE, and PR3, are indicated to interfere with SARS-CoV-2 infection. 28 Overall, protease inhibitors might be beneficial for treatment.…”

Correlation between α1-Antitrypsin Deficiency and SARS-CoV-2 Infection: Epidemiological Data and Pathogenetic Hypotheses

“…NE, an enzyme responsible for the proteolytic degradation of lung elastase and alveolar and interstitial lung tissue, and AAT, which primarily acts as an inhibitor of the serine protease, act in concert to maintain protease–anti-protease homeostasis, thus protecting the lung tissue from proteolytic digestion [ 10 ]. AAT also has anti-coagulation effects and can protect against inflammation, cell death, and the formation of neutrophil extracellular traps (NETs) [ 11 ]. Notably, AAT has the capacity to bind and inhibit the SARS-CoV-2-priming protease, transmembrane serine protease 2 (TMPRSS2), on host cells, thus inhibiting the first step in the SARS-CoV-2 cell cycle [ 12 ].…”

SARS-CoV-2 infection in alpha1-antitrypsin deficiency

“…In conclusion our study does not suggest any increased risk of SARS-CoV-2 infection or death associated with AATD, but additional prospective studies are needed for severe AATD before definitive conclusions can be made. Ongoing studies, that are exploring the usefulness of AAT augmentation for treatment of SARS-CoV-2 infection, will shed further light on the importance of AAT in this setting 8 , 9 .…”