Native and activated antithrombin inhibits TMPRSS2 activity and SARS‐CoV‐2 infection

Wettstein, Lukas; Immenschuh, Patrick; Conzelmann, Carina; Almeida-Hernández, Yasser; Hoffmann, Markus; Kempf, Amy; Nehlmeier, Inga; Lotke, Rishikesh; Petersen, Moritz; Stenger, Steffen; Kirchhoff, Frank; Sauter, Daniel; Pöhlmann, Stefan; Sánchez-García, Elsa; Münch, Jan

doi:10.1002/jmv.28124

Cited by 18 publications

(12 citation statements)

References 99 publications

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“…Serpin C1 suppressed SARS-CoV-2 replication in HBEC ALI cultures even more efficiently than Serpin A1 or E1 [ 39 ]. These findings were extended by Wettstein and colleagues, who demonstrated that Serpin C1 reduced not only the infectivity of viral particles carrying SARS-CoV-2 Spike but also virions carrying the Spike proteins of SARS-CoV, MERS-CoV and hCoV-229E [ 42 ]. As expected, virions pseudotyped with the protease-independent glycoprotein G of vesicular stomatitis virus (VSV) were not restricted.…”

Section: Endogenous Inhibitors Of Viral Glycoprotein Cleavagementioning

confidence: 78%

Restriction of Viral Glycoprotein Maturation by Cellular Protease Inhibitors

Lotke,

Petersen,

Sauter

2024

Viruses

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The human genome is estimated to encode more than 500 proteases performing a wide range of important physiological functions. They digest proteins in our food, determine the activity of hormones, induce cell death and regulate blood clotting, for example. During viral infection, however, some proteases can switch sides and activate viral glycoproteins, allowing the entry of virions into new target cells and the spread of infection. To reduce unwanted effects, multiple protease inhibitors regulate the proteolytic processing of self and non-self proteins. This review summarizes our current knowledge of endogenous protease inhibitors, which are known to limit viral replication by interfering with the proteolytic activation of viral glycoproteins. We describe the underlying molecular mechanisms and highlight the diverse strategies by which protease inhibitors reduce virion infectivity. We also provide examples of how viruses evade the restriction imposed by protease inhibitors. Finally, we briefly outline how cellular protease inhibitors can be modified and exploited for therapeutic purposes. In summary, this review aims to summarize our current understanding of cellular protease inhibitors as components of our immune response to a variety of viral pathogens.

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Section: Endogenous Inhibitors Of Viral Glycoprotein Cleavagementioning

confidence: 78%

Restriction of Viral Glycoprotein Maturation by Cellular Protease Inhibitors

Lotke,

Petersen,

Sauter

2024

Viruses

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“…Inhibiting the elastase activity also improves the adjuvanticity of the spike vaccine in vivo, suggesting that elastase may modulate spike antigen processing in the absence of membrane fusion [ 144 ]. Lastly, coagulation factors in the patient serum, such as factor Xa and thrombin, can directly cleave spikes at both S1/S2 and S2′ cleavage sites [ 145 , 146 ]; these factors may increase SARS-CoV-2 infection and exacerbate host pathology.…”

Section: Spike Proteolytic Activation and Utilization Of Host Proteasesmentioning

confidence: 99%

SARS-CoV-2 Spike-Mediated Entry and Its Regulation by Host Innate Immunity

et al. 2023

Viruses

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The constantly evolving severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOC) fuel the worldwide coronavirus disease (COVID-19) pandemic. The spike protein is essential for the SARS-CoV-2 viral entry and thus has been extensively targeted by therapeutic antibodies. However, mutations along the spike in SARS-CoV-2 VOC and Omicron subvariants have caused more rapid spread and strong antigenic drifts, rendering most of the current antibodies ineffective. Hence, understanding and targeting the molecular mechanism of spike activation is of great interest in curbing the spread and development of new therapeutic approaches. In this review, we summarize the conserved features of spike-mediated viral entry in various SARS-CoV-2 VOC and highlight the converging proteolytic processes involved in priming and activating the spike. We also summarize the roles of innate immune factors in preventing spike-driven membrane fusion and provide outlines for the identification of novel therapeutics against coronavirus infections.

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“…143 Recent molecular work indicates that the protective effect of AT against SARS-CoV-2 may occur at a very early stage of infection, as AT appears to inhibit the ability of SARS-CoV-2 to infect and replicate in lung epithelial cells. 144 Therefore, the effect of AT on COVID-19 pathophysiology may include anticoagulation, thromboprophylaxis, and protection against infection, but there are no current guidelines related to this application. Further studies with larger sample sizes are needed to determine if AT can improve outcomes for individuals with COVID-19.…”

Section: Covid-19mentioning

confidence: 99%

Antithrombin Therapy: Current State and Future Outlook

Rodgers,

Mahajerin

2023

Clin Appl Thromb Hemost

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Antithrombin (AT) is a natural anticoagulant pivotal in inactivating serine protease enzymes in the coagulation cascade, making it a potent inhibitor of blood clot formation. AT also possesses anti-inflammatory properties by influencing anticoagulation and directly interacting with endothelial cells. Hereditary AT deficiency is one of the most severe inherited thrombophilias, with up to 85% lifetime risk of venous thromboembolism. Acquired AT deficiency arises during heparin therapy or states of hypercoagulability like sepsis and premature infancy. Optimization of AT levels in individuals with AT deficiency is an important treatment consideration, particularly during high-risk situations such as surgery, trauma, pregnancy, and postpartum. Here, we integrate the existing evidence surrounding the approved uses of AT therapy, as well as potential additional patient populations where AT therapy has been considered by the medical community, including any available consensus statements and guidelines. We also describe current knowledge regarding cost-effectiveness of AT concentrate in different contexts. Future work should seek to identify specific patient populations for whom targeted AT therapy is likely to provide the strongest clinical benefit.

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Native and activated antithrombin inhibits TMPRSS2 activity and SARS‐CoV‐2 infection

Cited by 18 publications

References 99 publications

Restriction of Viral Glycoprotein Maturation by Cellular Protease Inhibitors

Restriction of Viral Glycoprotein Maturation by Cellular Protease Inhibitors

SARS-CoV-2 Spike-Mediated Entry and Its Regulation by Host Innate Immunity

Antithrombin Therapy: Current State and Future Outlook

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