Proteolysis and Deficiency of α1-Proteinase Inhibitor in SARS-CoV-2 Infection

The SARS-CoV-2 pandemic had stimulated the emergence of numerous publications on the α₁-proteinase inhibitor (α₁-PI, α₁-antitrypsin), especially when it was found that the regions of high mortality corresponded to the regions with deficient α₁-PI alleles. By analogy with the data obtained in the last century, when the first cause of the genetic deficiency of α₁-antitrypsin leading to elastase activation in pulmonary emphysema was proven, it can be supposed that proteolysis hyperactivation in COVID-19 may be associated with the impaired functions of α₁-PI. The purpose of this review was to systematize the scientific data and critical directions for translational studies on the role of α₁-PI in SARS-CoV-2-induced proteolysis hyperactivation as a diagnostic marker and a therapeutic target. This review describes the proteinase-dependent stages of viral infection: the reception and penetration of the virus into a cell and the imbalance of the plasma aldosterone-angiotensin-renin, kinin, and blood clotting systems. The role of ACE2, TMPRSS, ADAM17, furin, cathepsins, trypsin- and elastase-like serine proteinases in the virus tropism, the activation of proteolytic cascades in blood, and the COVID-19-dependent complications is considered. The scientific reports on α₁-PI involvement in the SARS-CoV-2-induced inflammation, the relationship with the severity of infection and comorbidities were analyzed. Particular attention is paid to the acquired α₁-PI deficiency in assessing the state of patients with proteolysis overactivation and chronic non-inflammatory diseases, which are accompanied by the risk factors for comorbidity progression and the long-term consequences of COVID-19. Essential data on the search and application of protease inhibitor drugs in the therapy for bronchopulmonary and cardiovascular pathologies were analyzed. The evidence of antiviral, anti-inflammatory, anticoagulant, and anti-apoptotic effects of α₁-PI, as well as the prominent data and prospects for its application as a targeted drug in the SARS-CoV-2 acquired pneumonia and related disorders, are presented.