No definitive treatment for
COVID-19 exists although promising results have been reported with
remdesivir and
glucocorticoids. Short of a truly effective preventive or curative
vaccine against SARS-CoV-2, it is becoming increasingly clear that multiple pathophysiologic processes seen with
COVID-19 as well as SARS-CoV-2 itself should be targeted. Because alpha-1-antitrypsin (AAT) embraces a panoply of biologic activities that may antagonize several pathophysiologic mechanisms induced by SARS-CoV-2, we hypothesize that this naturally occurring molecule is a promising agent to ameliorate
COVID-19. We posit at least seven different mechanisms by which AAT may alleviate
COVID-19. First, AAT is a
serine protease inhibitor (
SERPIN) shown to inhibit TMPRSS-2, the host
serine protease that cleaves the spike
protein of SARS-CoV-2, a necessary preparatory step for the virus to bind its
cell surface receptor ACE2 to gain intracellular entry. Second, AAT has anti-viral activity against other RNA viruses HIV and
influenza as well as induces autophagy, a known host effector mechanism against MERS-CoV, a related coronavirus that causes the
Middle East Respiratory Syndrome. Third, AAT has potent anti-inflammatory properties, in part through inhibiting both
nuclear factor-kappa B (NFκB) activation and ADAM17 (also known as
tumor necrosis factor-alpha converting enzyme), and thus may dampen the hyper-inflammatory response of
COVID-19. Fourth, AAT inhibits
neutrophil elastase, a
serine protease that helps recruit potentially injurious neutrophils and implicated in
acute lung injury. AAT inhibition of ADAM17 also prevents shedding of ACE2 and hence may preserve ACE2 inhibition of
bradykinin, reducing the ability of
bradykinin to cause a capillary leak in
COVID-19. Fifth, AAT inhibits
thrombin, and
venous thromboembolism and in situ microthrombi and macrothrombi are increasingly implicated in
COVID-19. Sixth, AAT inhibition of
elastase can antagonize the formation of neutrophil extracellular traps (NETs), a complex extracellular structure comprised of neutrophil-derived
DNA,
histones, and
proteases, and implicated in the
immunothrombosis of
COVID-19; indeed, AAT has been shown to change the shape and adherence of non-COVID-19-related NETs. Seventh, AAT inhibition of endothelial cell apoptosis may limit the endothelial injury linked to severe COVID-19-associated
acute lung injury, multi-organ dysfunction, and
pre-eclampsia-like syndrome seen in gravid women. Furthermore, because both NETs formation and the presence of anti-
phospholipid antibodies are increased in both
COVID-19 and non-COVID
pre-eclampsia, it suggests a similar vascular pathogenesis in both disorders. As a final point, AAT has an excellent safety profile when administered to patients with AAT deficiency and is dosed intravenously once weekly but also comes in an inhaled preparation. Thus, AAT is an appealing drug candidate to treat
COVID-19 and should be studied.