Nafamostat Mesylate Blocks Activation of SARS-CoV-2: New Treatment Option for COVID-19

Hoffmann, Markus; Schroeder, Simon; Kleine-Weber, Hannah; Müller, Marcel A.; Drosten, Christian; Pöhlmann, Stefan

doi:10.1128/aac.00754-20

Cited by 474 publications

(526 citation statements)

References 14 publications

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“…Nafamostat (Figure 2e) is a serine protease inhibitor currently in clinical trials for SARS-CoV2 infection in the light of its proposed ability to inhibit the transmembrane protease serine 2 (TMPRSS2)dependent host cell entry [29,30]. During our simulation (Video S3) nafamostat remained bound to the RBD pocket thanks to hydrogen bonds between the guanidinium group and N501, G502 and G496 (Figure 2e), as well as hydrophobic contacts with Y505 (MMGBSA binding energy = -29.8 ± 3.9).…”

Section: Cefsulodin Cromoglycate Nafamostat Nilotinib Pen Uridolmentioning

confidence: 99%

Supervised molecular dynamics for exploring the druggability of the SARS-CoV-2 spike protein

Deganutti

Prischi

Reynolds

2020

Preprint

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The recent outbreak of the respiratory syndrome-related coronavirus (SARS-CoV-2) is stimulating an unprecedented scientific campaign to alleviate the burden of the coronavirus disease (COVID-19). One line of research has focused on targeting SARS-CoV-2 proteins fundamental for its replication by repurposing drugs approved for other diseases. The first interaction between the virus and the host cell is mediated by the spike protein on the virus surface and the human angiotensin-converting enzyme (ACE2). Small molecules able to bind the receptor-binding domain (RBD) of the spike protein and disrupt the binding to ACE2 would offer an important tool for slowing, or even preventing, the infection. Here, we screened 2421 approved small molecules in silico and validated the docking outcomes through extensive molecular dynamics simulations. Out of six drugs characterized as putative RBD binders, the cephalosporin antibiotic cefsulodin was further assessed for its effect on the binding between the RBD and ACE2, suggesting the importance of considering the dynamic formation of the heterodimer when judging any potential candidate.

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Section: Cefsulodin Cromoglycate Nafamostat Nilotinib Pen Uridolmentioning

confidence: 99%

Supervised molecular dynamics for exploring the druggability of the SARS-CoV-2 spike protein

Deganutti

Prischi

Reynolds

2020

Preprint

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“…Recently determined structures of S in complex with ACE2 have confirmed the same folded receptor binding domain (RBD) in both S proteins, albeit slightly offset when compared with each other [4,5]. The SARS-CoV-2 S has a polybasic site upstream of the S fusion peptide and preliminary experiments show that proteolytic processing of S is required for cell entry [6,7]. S is the principle neutralizing determinant of the virus and is composed of two domains, S1 and S2.…”

Section: Introductionmentioning

confidence: 99%

Recombinant SARS-CoV-2 spike proteins for sero-surveillance and epitope mapping

Jegouic

Loureiro

Thom

et al. 2020

Preprint

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The newly emergent SARS-CoV-2 coronavirus is closely related to SARS-CoV which emerged in 2002. Studies on coronaviruses in general, and SARS in particular, have identified the virus spike protein (S) as being central to virus tropism, to the generation of a protective antibody response and to the unambiguous detection of past infections. As a result of this centrality SARS-CoV-2 S protein has a role in many aspects of research from vaccines to diagnostic tests. We describe a number of recombinant forms of SARS-CoV-2 S expressed in commonly available expression systems and their preliminary use in diagnostics and epitope mapping. These sources may find use in the current and future analysis of the virus and the Covid-19 disease it causes.

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“…47 TMPRSS is expressed on SARS-CoV target cells. 48 After subunit S1 of the spike binds to membrane bound ACE2, TMPRSS2 activates the spike and cleaves the ACE2 receptor. TMPRSS2 also acts on the S2 subunit, causing an irreversible conformational change facilitating fusion of the viral membrane with the host cell membrane and endocytosis.…”

Section: Ace2 and Covid-19mentioning

confidence: 99%

“…47 Camostat mesylate, a serine protease inhibitor used in Japan to treat chronic pancreatitis, inhibits TMPRSS2 and can block entry of SARS-CoV-2 into bronchial epithelial cells in vitro. 47,48 Angiotensin II. Many patients with severe COVID-19 infection admitted to ICU are in septic shock.…”

Section: Potential Covid-19 Treatment Involving Ace2 Systemmentioning

confidence: 99%

Coronavirus disease 2019 (COVID-19) and the renin-angiotensin system: A closer look at angiotensin-converting enzyme 2 (ACE2)

Zemlin

Wiese

2020

Ann Clin Biochem

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Since the first cases of atypical pneumonia linked to the Huanan Seafood Wholesale Market in Wuhan, China, were described in late December 2019, the global landscape has changed radically. In March 2020, the World Health Organization declared COVID-19 a global pandemic, and at the time of writing this review, just over three million individuals have been infected with more than 200,000 deaths globally. Numerous countries are in 'lockdown', social distancing is the new norm, even the most advanced healthcare systems are under pressure, and a global economic recession seems inevitable. A novel coronavirus (SARS-CoV-2) was identified as the aetiological agent. From experience with previous coronavirus epidemics, namely the severe acute respiratory syndrome (SARS) and Middle East Respiratory Syndrome (MERS) in 2004 and 2012 respectively, it was postulated that the angiotensin-converting enzyme-2 (ACE2) receptor is a possible port of cell entry. ACE2 is part of the renin-angiotensin system and is also associated with lung and cardiovascular disorders and inflammation. Recent studies have confirmed that ACE2 is the port of entry for SARS-CoV-2. Male sex, advanced age and a number of associated comorbidities have been identified as risk factors for infection with COVID-19. Many high-risk COVID-19 patients with comorbidities are on ACE inhibitors and angiotensin receptor blockers, and this has sparked debate about whether to continue these treatment regimes. Attention has also shifted to ACE2 being a target for future therapies or vaccines against COVID-19. In this review, we discuss COVID-19 and its complex relationship with ACE2.

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Nafamostat Mesylate Blocks Activation of SARS-CoV-2: New Treatment Option for COVID-19

Cited by 474 publications

References 14 publications

Supervised molecular dynamics for exploring the druggability of the SARS-CoV-2 spike protein

Supervised molecular dynamics for exploring the druggability of the SARS-CoV-2 spike protein

Recombinant SARS-CoV-2 spike proteins for sero-surveillance and epitope mapping

Coronavirus disease 2019 (COVID-19) and the renin-angiotensin system: A closer look at angiotensin-converting enzyme 2 (ACE2)

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