Abstract
Camostat, nafamostat, and bromhexine are inhibitors of the transmembrane serine protease TMPRSS2. The inhibition of TMPRSS2 has been shown to prevent the viral infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other viruses. However, while camostat and nafamostat inhibit TMPRSS2 by forming a covalent adduct, the mode of action of bromhexine remains unclear. TMPRSS2 is autocatalytically activated from its inactive form, zymogen, through a proteolytic cleavage that promotes the binding of Ile256 to a putative allosteric pocket (A-pocket). Computer simulations, reported here, indicate that Ile256 binding induces a conformational change in the catalytic site, thus providing the atomistic rationale to the activation process of the enzyme. Furthermore, computational docking and molecular dynamics simulations indicate that bromhexine competes with the N-terminal Ile256 for the same binding site, making it a potential allosteric inhibitor. Taken together, these findings provide the atomistic basis for the development of more selective and potent TMPRSS2 inhibitors.
Highlights
Since the early days of the pandemic coronavirus disease 2019 (COVID-19) started from the Chinese city of Wuhan, Hubei province, in December 2019, many reports highlighted the crucial role of transmembrane serine protease 2 (TMPRSS2) in the spread and progression of the viral infection (Hoffmann et al, 2020; Sungnak et al, 2020)
TMPRSS2 has been put in relation with the spread of other viruses, such as influenza A viruses, severe acute respiratory syndrome coronavirus 2 (SARS-CoV), and Middle East respiratory syndrome coronavirus (MERS-CoV), and it has been studied as a potential therapeutic target for prostate cancer therapy (Lucas et al, 2014; Shen et al, 2017)
As TMPRSS2 expression is regulated by the androgen receptor, it has been hypothesized that its crucial role in the viral infection might help explain why males have more frequently severe complications and a worse clinical outcome than females and if androgen deprivation therapy (ADT) can have a protective effect against SARS-CoV-2 infection (Montopoli et al, 2020)
Summary
Since the early days of the pandemic coronavirus disease 2019 (COVID-19) started from the Chinese city of Wuhan, Hubei province, in December 2019, many reports highlighted the crucial role of transmembrane serine protease 2 (TMPRSS2) in the spread and progression of the viral infection (Hoffmann et al, 2020; Sungnak et al, 2020). As TMPRSS2 expression is regulated by the androgen receptor, it has been hypothesized that its crucial role in the viral infection might help explain why males have more frequently severe complications and a worse clinical outcome than females and if androgen deprivation therapy (ADT) can have a protective effect against SARS-CoV-2 infection (Montopoli et al, 2020). Besides the generation of a reliable model of the TMPRSS2 catalytic domain, the results of our investigations confirmed that both camostat and nafamostat are competitive inhibitors efficiently binding the active site. They indicated that the binding of BH to the active site is unlikely, leading us to the identification of a putative allosteric binding pocket
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