Aprotinin Inhibits SARS-CoV-2 Replication

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

doi:10.3390/cells9112377

Cited by 72 publications

(98 citation statements)

References 46 publications

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“…Two studies showed AAT-dependent inhibition of entry of pseudotyped VSV or SARS-CoV-2 into airway cells (24)(25)(26). Another study could not detect a significant effect of AAT in cell-based SARS-CoV-2 infection models (27). Differences within the cell models likely contribute to this variation.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic application of alpha-1-antitrypsin in COVID-19

Ritzmann

Chitirala

Yao

et al. 2021

Preprint

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Rationale: The treatment options for COVID-19 patients are sparse and do not show sufficient efficacy. Alpha-1-antitrypsin (AAT) is a multi-functional host-defense protein with anti-proteolytic and anti-inflammatory activities. Objectives: The aim of the present study was to evaluate whether AAT is a suitable candidate for treatment of COVID-19. Methods: AAT and inflammatory markers were measured in the serum of COVID-19 patients. Human cell cultures were employed to determine the cell-based anti-protease activity of AAT and to test whether AAT inhibits the host cell entry of vesicular stomatitis virus (VSV) particles bearing the spike (S) protein of SARS-CoV-2 and the replication of authentic SARS-CoV-2. Inhaled and / or intravenous AAT was applied to nine patients with mild-to-moderate COVID-19. Measurements and Main Results: The serum AAT concentration in COVID-19 patients was increased as compared to control patients. The relative AAT concentrations were decreased in severe COVID-19 or in non-survivors in ratio to inflammatory blood biomarkers. AAT inhibited serine protease activity in human cell cultures, the uptake of VSV-S into airway cell lines and the replication of SARS-CoV-2 in human lung organoids. All patients, who received AAT, survived and showed decreasing respiratory distress, inflammatory markers, and viral load. Conclusion: AAT has anti-SARS-CoV-2 activity in human cell models, is well tolerated in patients with COVID-19 and together with its anti-inflammatory properties might be a good candidate for treatment of COVID-19.

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Section: Discussionmentioning

confidence: 99%

Therapeutic application of alpha-1-antitrypsin in COVID-19

Ritzmann

Chitirala

Yao

et al. 2021

Preprint

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“…We also corroborated this trend at the protein level in Caco-2 cells. During the preparation of these manuscript, a study from Bojkova D et al, 2020 was published suggesting a possible role of SPINT1, SPINT2 and SERPINA1 in viral infection by observing the down-regulation of their protein levels in infected cells and also by evaluating the effect of Aprotinin a non-specific SP inhibitor on viral load 6 . However, here for the first time by knocking down SPINT2 , we provide a direct causal evidence that SPINT2 is indeed able to modulate SARS-CoV-2 infection.…”

Section: Discussionmentioning

confidence: 99%

“…SARS-CoV-2 entry requires a two-step process: first, the envelope protein spike (S) binds to the viral cellular receptor Angiotensin-converting enzyme 2 (ACE2) membrane protein 1 and is then proteolytically activated by cellular serine proteases like TMPRSS2, TMPRSS4 and Furin 2–4 . TMPRSS2 has been proposed as a putative drug target 3,5,6 and as a biomarker for COVID19 disease severity 7,8 . Despite its central role, the regulation of TMPRSS2 is poorly understood, although its activation by androgen response elements has been documented in normal and tumor prostate tissues 9 .…”

Section: Introductionmentioning

confidence: 99%

SPINT2 controls SARS-CoV-2 viral infection and is associated to disease severity

Alvarez

Sharma

Kee

et al. 2020

Preprint

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COVID-19 outbreak is the biggest threat to human health in recent history. Currently, there are over 1.5 million related deaths and 75 million people infected around the world (as of 22/12/2020). The identification of virulence factors which determine disease susceptibility and severity in different cell types remains an essential challenge. The serine protease TMPRSS2 has been shown to be important for S protein priming and viral entry, however, little is known about its regulation. SPINT2 is a member of the family of Kunitz type serine protease inhibitors and has been shown to inhibit TMPRSS2. Here, we explored the existence of a co-regulation between SPINT2/TMPRSS2 and found a tightly regulated protease/inhibitor expression balance across tissues. We found that SPINT2 negatively correlates with SARS-CoV-2 expression in Calu-3 and Caco-2 cell lines and was down-regulated in secretory cells from COVID-19 patients. We validated our findings using Calu-3 cell lines and observed a strong increase in viral load after SPINT2 knockdown. Additionally, we evaluated the expression of SPINT2 in datasets from comorbid diseases using bulk and scRNA-seq data. We observed its down-regulation in colon, kidney and liver tumors as well as in alpha pancreatic islets cells from diabetes Type 2 patients, which could have implications for the observed comorbidities in COVID-19 patients suffering from chronic diseases.

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“…This mechanism of Aprotinin's action suggests that it can prevent SARS-CoV-2 penetration into susceptible cells [14]. Recently, it was shown that Aprоtinin also inhibits replication of SARS-CoV-2 by downregulating cellular protease during replication cycles [15].…”

Section: Introductionmentioning

confidence: 99%

Aprotinin is a potent multi-target drug for the combination therapy of moderate COVID-19 cases

Ivashchenko¹,

Azarova²,

Egorova³

et al. 2020

Preprint

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Objectives. COVID-19 is a contagious multisystem inflammatory disease caused by a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We have studied the efficacy of Aprotinin (nonspeciﬁc serine proteases inhibitor) and Avifavir or Hydroxychloroquine (HCQ) combinations for the therapy of COVID-19. Methods. Three prospective single-center (cohorts 1 – 3) studies included participants with moderate COVID-19-related pneumonia, laboratory-confirmed SARS-CoV-2 and admitted to the hospitals. Patients received combinations of intravenous (IV) Aprotinin (1,000,000 KIU daily, 3 days) and HCQ (cohort 1), inhalation (inh) treatment with Aprotinin (625 KIU 4 times per day, 5 days) and HCQ (cohort 2) or IV Aprotinin (1,000,000 KIU daily for 5 days) and Avifavir (cohort 3). Results. In the cohorts 1 – 3, the combination therapy showed 100% efficacy in preventing the transfer of patients (n = 30) to the intensive care unit (ICU). The effect of combination therapy in the cohort 3 was the most prominent and the median time to SARS-CoV-2 elimination was 3.5 days (IQR 3.0 – 4.0), normalization of CRP concentration was 3.5 days (IQR 3 – 5), of D-dimer concentration - 5 days (IQR 4 – 5); body temperature - 1 day (IQR 1 – 3), improvement in clinical status or discharge from the hospital - 5 days (IQR 5 – 5), and improvement in lung lesions of patients on 14 day - 100%. Conclusions. The administration of Aprotinin combinations prevented the transfer of moderate COVID-19 patients to the ICU for mechanical ventilation (ALV) or non-invasive ventilation (NIV) and by shortening of their hospital stay.

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Aprotinin Inhibits SARS-CoV-2 Replication

Cited by 72 publications

References 46 publications

Therapeutic application of alpha-1-antitrypsin in COVID-19

Therapeutic application of alpha-1-antitrypsin in COVID-19

SPINT2 controls SARS-CoV-2 viral infection and is associated to disease severity

Aprotinin is a potent multi-target drug for the combination therapy of moderate COVID-19 cases

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