Antiviral and Anti-inflammatory Effects of Alpha-1-Antitrypsin in the Treatment of COVID-19
Human alpha-1-antitrypsin (AAT) is a circulating blood glycoprotein that has been used for decades in the treatment of patients with AAT deficiency, lung damage, and emphysema, helping to prevent acute lung injury. Recently, it has been found that AAT also mitigates the course of COVID-19 disease by hindering the entry of the SARS-CoV-2 coronavirus into host cells. This dual antiviral and anti-inflammatory action makes AAT an excellent candidate for COVID-19 treatment.
Mechanism of AAT Action in COVID-19 Infection
The entry of SARS-CoV-2 and other coronaviruses into host cells occurs through the binding of the viral S protein to angiotensin-converting enzyme 2 (ACE2) on the surface of host cells, mediated by transmembrane serine protease 2 (TMPRSS2). AAT is a physiological protease inhibitor and is capable of dose-dependent inhibition of the proteolytic activity of TMPRSS2, thereby specifically hindering the entry of SARS-CoV-2 into cells.
In addition to these antiprotease effects, AAT also has anti-inflammatory effects, which include improving mitochondrial membrane stability, inhibiting apoptosis, inhibiting the activation of nuclear factor kappa B (NF-κB), and modulating the balance between pro- and anti-inflammatory cytokines, hence promoting immunological tolerance. Additionally, AAT inhibits thrombin and plays a role in regulating proteases involved in fibrinolysis, thereby preventing hyperactivation of the coagulation cascade.
Implications for Practice
Three clinical studies have already been approved in several countries to further elucidate the therapeutic effect of AAT in patients with COVID-19. These studies will test whether AAT can prevent the progression from a mild course of COVID-19 to severe lung damage and whether it can be potentially used in the treatment of patients with COVID-19 and acute respiratory failure.
(epa)
Source: Yang C., Keshavjee S., Liu M. Alpha-1 antitrypsin for COVID-19 treatment: dual role in antiviral infection and anti-inflammation. Front Pharmacol 2020 Dec 11; 11: 615398, doi: 10.3389/fphar.2020.615398.
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