Hypothesis: Alpha-1-antitrypsin is a promising treatment option for COVID-19

Abstract

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.

Keywords: Anti-inflammation; Anti-thrombosis; NETs; SARS-CoV-2; SERPIN; Serine protease.

Fig. 1

Hypothesized mechanisms by alpha-1-antitrypsin (AAT) may be therapeutically efficacious against COVID-19. We hypothesize that AAT is a promising therapeutic against COVID-19 via at least seven mechanisms (see accompanying text for full description). In brief, we posit that AAT will: (1) augment host immunity against SARS-CoV-2 by enhancing autophagy, (2) inhibit TMPRSS-2 activity, mitigating a key and necessary step prior to SARS-CoV-2 entry into cells, (3) antagonize inflammation, (4) inhibit neutrophil elastase and ameliorate acute lung injury, (5) inhibit thrombin, retarding microthrombi formation, (6) inhibit neutrophil extracellular traps (NETs) adherence, limiting immunothrombosis seen with COVID-19, and (7) protect against endothelial cell apoptosis, curbing COVID-19-associated endothelial injury. Whereas TMPRSS-2 may also process ACE2 to facilitate binding and entry of SARS-CoV, it is not known whether such activity also enhances SARS-CoV-2 binding to ACE2; this uncertainly is denoted by the question mark. ACE2 = receptor for SARS-CoV-2; TMPRSS-2 = serine protease necessary to “activate” SARS-CoV-2; T-shaped “arrows” = inhibition; red heptagon = SARS-CoV-2. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

The two faces of ACE2, ADAM17, and RAA inhibitors. (A) In blood vessels, angiotensin converting enzyme (ACE) converts angiotensin I (A-I) to angiotensin II (A-II). ACE2 then metabolizes A-I and A-II into angiotensin-(1–7) and angiotensin-(1–9), with the latter metabolites also known as pro-resolution peptides because, unlike A-II, they have anti-inflammatory, anti-fibrotic, and vasodilatory properties. (B) In the nasal and lung epithelium, ACE2 is the receptor for SARS-CoV-2 after the viral spike protein is processed by the serine protease TMPRSS-2. However, ACE2 is also anti-inflammatory and protects against various forms of acute lung injury through metabolism of pro-inflammatory A-II to anti-inflammatory angiotensin-(1–7) and angiotensin-(1–9), inhibition of bradykinin production, and preservation of cell viability but the precise ligand in the airways that ACE2 catalyzes is not known. ADAM17 is pro-inflammatory in that it converts membrane TNFα to soluble TNFα as well as causes shedding of ACE2, reducing the latter’s anti-inflammatory effects. Thus, (C) the two faces of ACE2 are that it is the receptor for SARS-CoV-2 and yet is anti-inflammatory and protects against lung injury. ADAM17 causes ACE2 shedding, reducing cell surface expression of the SARS-CoV-2 receptor but also induces a pro-inflammatory state. Inhibition of the renin-angiotensin-aldosterone (RAA) axis is also known to induce ACE2 expression but inhibits inflammation by reducing A-II expression. Thus, both RAA inhibition and AAT would increase ACE2 expression but both would inhibit A-II expression and inflammation. A-I = angiotensin I; A-II = angiotensin II; BK = bradykinin; RAA = renin-angiotensin-aldosterone; mTNFα = membrane-bound tumor necrosis factor-alpha; sTNFα = soluble TNFα; TACE = TNFα converting enzyme; Negative sign = inhibit or reduce; Positive sign = augment.

Fig. 3

Potential use of AAT depending on the severity. If more evidence acrue that AAT has great potential against SARS-CoV-2 infection and COVID-19 complications, AAT should be studied in patients with SARS-CoV-2 infection by randomized, placebo-controlled trials with AAT administered by different means depending on the severity of the SARS-CoV-2 infection. As shown, (A) AAT administered intravenously (IV) in critically-ill COVID-19 subjects, (B) AAT administered by nebulization in non-critically-ill patients with COVID-19 pneumonia, or (C) AAT administered prophylactically by a nasal spray (yet-to-be-developed) in asymptomatic persons with multiple risk factors for severe COVID-19 with unavoidable close contacts with COVID-19 positive individuals. AAT = alpha-1-antitrypsin.