Alpha-1-antitrypsin antagonizes COVID-19: a review of the epidemiology, molecular mechanisms, and clinical evidence

Abstract

Alpha-1-antitrypsin (AAT), a serine protease inhibitor (serpin), is increasingly recognized to inhibit SARS-CoV-2 infection and counter many of the pathogenic mechanisms of COVID-19. Herein, we reviewed the epidemiologic evidence, the molecular mechanisms, and the clinical evidence that support this paradigm. As background to our discussion, we first examined the basic mechanism of SARS-CoV-2 infection and contend that despite the availability of vaccines and anti-viral agents, COVID-19 remains problematic due to viral evolution. We next underscored that measures to prevent severe COVID-19 currently exists but teeters on a balance and that current treatment for severe COVID-19 remains grossly suboptimal. We then reviewed the epidemiologic and clinical evidence that AAT deficiency increases risk of COVID-19 infection and of more severe disease, and the experimental evidence that AAT inhibits cell surface transmembrane protease 2 (TMPRSS2) — a host serine protease required for SARS-CoV-2 entry into cells — and that this inhibition may be augmented by heparin. We also elaborated on the panoply of other activities of AAT (and heparin) that could mitigate severity of COVID-19. Finally, we evaluated the available clinical evidence for AAT treatment of COVID-19.

The Inhibition of Serine Proteases by Serpins Is Augmented by Negatively Charged Heparin: A Concise Review of Some Clinically Relevant Interactions

“…Detailed in silico modeling demonstrated the following: (i) there is a suboptimal electrostatic complementarity between AAT and TMPRSS2 (adjacent electropositive blue patches) at both the buried interface and the solvent-exposed interface rim in a molecular charge model (Figure 3A) that is stabilized by bridging negatively charged heparin molecules (Figure 3A, multi-colored stick figures); (ii) the RCL of AAT (Figure 3B, magenta) adopts an inhibitory-competent conformation compared with the crystal structure of TMPRSS2 (Figure 3B, cyan); superimposed is the bound exogenous inhibitor of TMPRSS2 (nafamostat) (Figure 3B, wheat) or the endogenous inhibitor of TMPRSS2 (HAI-2) (Figure 3C, wheat); and (iii) negatively charged heparin (Figure 3D, gray stick figures) bridges the adjacent electropositive amino acid residues (K = lysine, R = arginine) at the TMPRSS2-AAT interface, neutralizing otherwise repulsive forces [18]. We posit that the combination of AAT and enoxaparin will be more effective against COVID-19 than agents that only inhibit TMPRSS2 such as camostat [64], because AAT and enoxaparin individually and synergistically antagonize the SARS-CoV-2 infection and several other pathogenic mechanisms of COVID-19 (e.g., AAT is anti-inflammatory, inhibits neutrophil elastase, and protects against endothelial cell death, whereas heparin inhibits coagulation, is anti-inflammatory, competitively inhibits SARS-CoV-2 from binding to heparan sulfate (a co-receptor for SARS-CoV-2), and augments the C1-INH inhibition of kallikrein, preventing both bradykinin formation and capillary leak [72]).…”

“…Alpha-1-antitrypsin Proteinase-3, trypsin, chymotrypsin, myeloperoxidase, cathepsins, a-defensins, tryptase, plasmin, thrombin, factor Xa, urokinase, a disintegrin and metalloprotease 17 (ADAM17, aka tumor necrosis factor converting enzyme), and Transmembrane Protease 2 (TMPRSS2) [18,72,100,101].…”

Screening of Small-Molecule Libraries Using SARS-CoV-2-Derived Sequences Identifies Novel Furin Inhibitors

“…α1-PDX blocks the processing of HIV-1 and measles virus envelope glycoproteins and therefore viral spread [26]. Accordingly, α1-PDX antagonizes COVID-19 as well [27]. Peptide-based inhibitors represent an attractive alternative to large molecules because they are cheaper and easier to synthesize and deliver.…”

Analysis of alpha‐1‐antitrypsin (AAT)‐regulated, glucocorticoid receptor‐dependent genes in macrophages reveals a novel host defense function of AAT

“…Alpha‐1‐antitrypsin (AAT), the most abundant serine protease inhibitor (serpin) in circulation, is produced and secreted mainly by hepatocytes, but also by other cell types, including intestinal cells, lung alveolar cells, neutrophils, and macrophages (Janciauskiene et al., 2018 ; Pini et al., 2014 ). The best‐known function of AAT is the irreversible inhibition of elastase, but AAT also binds and inactivates other serine proteases such as proteinase‐3, trypsin, chymotrypsin, myeloperoxidase, cathepsins, α‐defensins, tryptase, plasmin, thrombin, factor Xa, urokinase, ADAM17 (a disintegrin and metalloprotease 17, aka tumor necrosis factor converting enzyme), and Transmembrane Protease 2 (TMPRSS2) (Bai et al., 2023 ; Bai, Buckle, et al., 2022 ; Frenzel et al., 2015 ; O'Brien et al., 2022 ). AAT has other biological functions that are less well appreciated; among these are anti‐inflammatory and host defense properties (Bai et al., 2019 ; Bai, Bai, et al., 2022 ; Jonigk et al., 2013 ; Lewis, 2012 ; Wanner et al., 2012 ).…”