Aprotinin Inhibits SARS-CoV-2 Replication

Denisa Bojkova,Sandra Ciesek,Marco Bechtel,Martin Michaelis,Danny Jonigk,Jake E Mcgreig,Gernot Rohde,Jindrich Cinatl,Kevin Klann,Katie-May Mclaughlin,Carla Bellinghausen,Mark N Wass,Christian Münch,Peter Braubach

doi:10.3390/cells9112377

Abstract

Severe acute respiratory syndrome virus 2 (SARS-CoV-2) is the cause of the current coronavirus disease 19 (COVID-19) pandemic. Protease inhibitors are under consideration as virus entry inhibitors that prevent the cleavage of the coronavirus spike (S) protein by cellular proteases. Herein, we showed that the protease inhibitor aprotinin (but not the protease inhibitor SERPINA1/alpha-1 antitrypsin) inhibited SARS-CoV-2 replication in therapeutically achievable concentrations. An analysis of proteomics and translatome data indicated that SARS-CoV-2 replication is associated with a downregulation of host cell protease inhibitors. Hence, aprotinin may compensate for downregulated host cell proteases during later virus replication cycles. Aprotinin displayed anti-SARS-CoV-2 activity in different cell types (Caco2, Calu-3, and primary bronchial epithelial cell air–liquid interface cultures) and against four virus isolates. In conclusion, therapeutic aprotinin concentrations exert anti-SARS-CoV-2 activity. An approved aprotinin aerosol may have potential for the early local control of SARS-CoV-2 replication and the prevention of COVID-19 progression to a severe, systemic disease.

Highlights

IntroductionSevere acute respiratory syndrome virus 2 (SARS-CoV-2), a novel betacoronavirus, causes a respiratory disease and pneumonia called coronavirus disease 19 (COVID-19) and is the cause of a current pandemic responsible for millions of cases and hundreds of thousands of deaths [1,2,3,4,5,6,7]
Severe acute respiratory syndrome virus 2 (SARS-CoV-2), a novel betacoronavirus, causes a respiratory disease and pneumonia called coronavirus disease 19 (COVID-19) and is the cause of a current pandemic responsible for millions of cases and hundreds of thousands of deaths [1,2,3,4,5,6,7].Drugs for the treatment of COVID-19 are urgently needed.Cell entry of coronaviruses is mediated by the interaction of the viral spike (S) protein with their host cell receptors, which differ between different coronaviruses [8]
We compared the anti-SARS-CoV-2 activity of aprotinin [15,26] and SERPINA1/alpha-1 antitrypsin, an endogenous protease inhibitor that is available as a pharmaceutical preparation for the treatment of alpha-1 antitrypsin deficiency [27], against three different SARS-CoV-2 isolates from two lineages (L: SARS-CoV-2/FFM1 and SARS-CoV-2/FFM2; GR: SARS-CoV-2/FFM6) [18]

Summary

Introduction

Severe acute respiratory syndrome virus 2 (SARS-CoV-2), a novel betacoronavirus, causes a respiratory disease and pneumonia called coronavirus disease 19 (COVID-19) and is the cause of a current pandemic responsible for millions of cases and hundreds of thousands of deaths [1,2,3,4,5,6,7]. Cell entry of coronaviruses is mediated by the interaction of the viral spike (S) protein with their host cell receptors, which differ between different coronaviruses [8]. Middle East respiratory syndrome coronavirus (MERS-CoV) uses dipeptidyl peptidase 4 (DPP4) as a cellular receptor [8]. Host cell entry of SARS-CoV-2 and of the closely related severe acute respiratory syndrome virus (SARS-CoV) is mediated by angiotensin-converting enzyme 2 (ACE2) [8,9,10]. S binding to ACE2 depends on S cleavage at three sites (S1, S2, and S2’) by host cell proteases, typically by the transmembrane serine protease 2 (TMPRSS2), and can be inhibited by serine protease inhibitors [9,10]

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