The Antiviral Potential of Host Protease Inhibitors

Steinmetzer, Torsten; Hardes, Kornelia

doi:10.1007/978-3-319-75474-1_11

Cited by 25 publications

(24 citation statements)

References 207 publications

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“…Unfortunately, there is no crystal structure of TMPRSS2 available so far, which prohibits a rational structure-based design of more efficient inhibitors of this protease. However, first homology models have been established, which may help for the development of improved TMPRSS2 inhibitors in the future ( 49 , 50 Preprint ).…”

Section: Discussionmentioning

confidence: 99%

“…Very effective furin inhibitors containing a C-terminal 4-amidinobenzylamide residue have been developed in recent years. Several of these analogs have been successfully used to inhibit the replication of numerous furin dependent human pathogenic viruses such as H5N1 influenza A virus, Chikungunya virus, West Nile virus and dengue-2 virus, mumps virus or respiratory syncytial virus (reviewed in references 49 , 55 , and 56 ). So far, these inhibitors have been used only in virus-infected cell cultures and not in animal models.…”

Section: Discussionmentioning

confidence: 99%

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TMPRSS2 and furin are both essential for proteolytic activation of SARS-CoV-2 in human airway cells

et al. 2020

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The novel emerged SARS-CoV-2 has rapidly spread around the world causing acute infection of the respiratory tract (COVID-19) that can result in severe disease and lethality. For SARS-CoV-2 to enter cells, its surface glycoprotein spike (S) must be cleaved at two different sites by host cell proteases, which therefore represent potential drug targets. In the present study, we show that S can be cleaved by the proprotein convertase furin at the S1/S2 site and the transmembrane serine protease 2 (TMPRSS2) at the S2′ site. We demonstrate that TMPRSS2 is essential for activation of SARS-CoV-2 S in Calu-3 human airway epithelial cells through antisense-mediated knockdown of TMPRSS2 expression. Furthermore, SARS-CoV-2 replication was also strongly inhibited by the synthetic furin inhibitor MI-1851 in human airway cells. In contrast, inhibition of endosomal cathepsins by E64d did not affect virus replication. Combining various TMPRSS2 inhibitors with furin inhibitor MI-1851 produced more potent antiviral activity against SARS-CoV-2 than an equimolar amount of any single serine protease inhibitor. Therefore, this approach has considerable therapeutic potential for treatment of COVID-19.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

TMPRSS2 and furin are both essential for proteolytic activation of SARS-CoV-2 in human airway cells

et al. 2020

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“…Previous studies have shown that it has some efficacy in respiratory infections. Bromhexine causes a decrease in the severity of this infection by acting on mucus production, mucus clearance, and enhancement of anti-biotic penetration [ 164 , 165 ]. The host proteases play an important role in the pathogenicity of various viruses such as influenza viruses, Ebola viruses, and coronaviruses through different mechanisms [ 166 ].…”

Section: Pharmacological Treatments Of Covid-19mentioning

confidence: 99%

Pharmacological treatments of COVID-19

et al. 2020

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The viral infection due to the new coronavirus or coronavirus disease 2019 (COVID-19), which was reported for the first time in December 2019, was named by the World Health Organization (WHO) as Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV2), because of the very similar genome and also its related symptoms to SARS-CoV1. The ongoing COVID-19 pandemic with significant mortality, morbidity, and socioeconomic impact is considered by the WHO as a global public health emergency. Since there is no specific treatment available for SARS-CoV2 infection, and or COVID-19, several clinical and sub-clinical studies are currently undertaken to find a gold-standard therapeutic regimen with high efficacy and low side effect. Based on the published scientific evidence published to date, we summarized herein the effects of different potential therapies and up-to-date clinical trials. The review is intended to help readers aware of potentially effective COVID-19 treatment and provide useful references for future studies.

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“…There are 588 human proteases listed in the degradome database: 81 192 metalloproteases, 184 serine proteases, 164 cysteine proteases, 27 threonine, and 21 aspartyl proteases. 82 Transmembrane serine proteases (TTSP) can be classified into three groups on the basis of transmembrane domain structure: Type I, which has a carboxy-terminal transmembrane domain; Type II, which has an amino-terminal transmembrane domain spanning through the cytosol; Type III, which anchors to the membrane by glycosyl-phosphatidylinositol (GPI). 83 The Type II group of serine proteases has 20 proteases that are subdivided into four subfamilies: hepsin/transmembrane protease/serine (TMPRSS), human airway trypsin-like (HAT)/differentially expressed in squamous cell carcinoma (DESC), matriptase, and Corin.…”

Section: Host Proteasesmentioning

confidence: 99%

Targeting Crucial Host Factors of SARS-CoV-2

et al. 2020

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Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread worldwide since its first incidence in Wuhan, China, in December 2019. Although the case fatality rate of COVID-19 appears to be lower than that of SARS and Middle East respiratory syndrome (MERS), the higher transmissibility of SARS-CoV-2 has caused the total fatality to surpass other viral diseases, reaching more than 1 million globally as of October 6, 2020. The rate at which the disease is spreading calls for a therapy that is useful for treating a large population. Multiple intersecting viral and host factor targets involved in the life cycle of the virus are being explored. Because of the frequent mutations, many coronaviruses gain zoonotic potential, which is dependent on the presence of cell receptors and proteases, and therefore the targeting of the viral proteins has some drawbacks, as strain-specific drug resistance can occur. Moreover, the limited number of proteins in a virus makes the number of available targets small. Although SARS-CoV and SARS-CoV-2 share common mechanisms of entry and replication, there are substantial differences in viral proteins such as the spike (S) protein. In contrast, targeting cellular factors may result in a broader range of therapies, reducing the chances of developing drug resistance. In this Review, we discuss the role of primary host factors such as the cell receptor angiotensin-converting enzyme 2 (ACE2), cellular proteases of S protein priming, post-translational modifiers, kinases, inflammatory cells, and their pharmacological intervention in the infection of SARS-CoV-2 and related viruses.

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The Antiviral Potential of Host Protease Inhibitors

Cited by 25 publications

References 207 publications

TMPRSS2 and furin are both essential for proteolytic activation of SARS-CoV-2 in human airway cells

TMPRSS2 and furin are both essential for proteolytic activation of SARS-CoV-2 in human airway cells

Pharmacological treatments of COVID-19

Targeting Crucial Host Factors of SARS-CoV-2

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