TMPRSS2 binds TMPRSS2 inhibitors

Stable Identifier
Reaction [binding]
Homo sapiens
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Entry of influenza, parainfluenza and coronaviruses into airway epithelial cells requires binding of a viral spike protein to a host cell receptor, followed by cleavage and activation of the viral spike protein mediated by the host cell. Without this cleavage, fusion of the viral and host cell membranes is blocked. The primary receptor for the human SARS-CoV-1 virus is angiotensin converting enzyme 2 (ACE2) (Li et al. 2003). The resultant complex is cleaved by the protease transmembrane protease serine 2 (TMPRSS2) (Shulla et al. 2011, Heurich et al. 2014). Therefore, active site inhibitors of these airway proteases could have broad therapeutic applicability against multiple respiratory viruses (Laporte & Naesens 2017). The approved drug camostat is a protease inhibitor that may block SARS-CoV-2 entry into cells by inhibiting the actions of TMPRSS2 (Kawase et al. 2012, Hoffmann et al. 2020). Nafamostat, another serine protease inhibitor, was found to be a potent inhibitor of S-mediated membrane fusion and blocked MERS-CoV infection in vitro (Yamamoto et al. 2016).

Otamixaban (FXV673), an anticoagulant, is a potent and selective direct inhibitor of coagulation factor Xa. Virtual docking studies suggest that otamixaban may bind to the serine protease TMPRSS2 (Rensi et al. 2020, preprint). Inhibition of TMPRSS2 is being examined for antiviral activity but its inhibitory potential and/or antiviral activity have not yet been determined so it is annotated here as a candidate drug. I-432 is another inhibitor of TMPRSS2 under investigation for anti viral potential (Pászti-Gere et al. 2016).

Literature References
PubMed ID Title Journal Year
32142651 SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Hoffmann, M, Kleine-Weber, H, Schroeder, S, Krüger, N, Herrler, T, Erichsen, S, Schiergens, TS, Herrler, G, Wu, NH, Nitsche, A, Müller, MA, Drosten, C, Pöhlmann, S

Cell 2020
22496216 Simultaneous treatment of human bronchial epithelial cells with serine and cysteine protease inhibitors prevents severe acute respiratory syndrome coronavirus entry

Kawase, M, Shirato, K, van der Hoek, L, Taguchi, F, Matsuyama, S

J. Virol. 2012
24227843 TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein

Heurich, A, Hofmann-Winkler, H, Gierer, S, Liepold, T, Jahn, O, Pöhlmann, S

J. Virol. 2014
27277342 In vitro characterization of TMPRSS2 inhibition in IPEC-J2 cells

Pászti-Gere, E, Czimmermann, E, Ujhelyi, G, Balla, P, Maiwald, A, Steinmetzer, T

J Enzyme Inhib Med Chem 2016
27550352 Identification of Nafamostat as a Potent Inhibitor of Middle East Respiratory Syndrome Coronavirus S Protein-Mediated Membrane Fusion Using the Split-Protein-Based Cell-Cell Fusion Assay

Yamamoto, M, Matsuyama, S, Li, X, Takeda, M, Kawaguchi, Y, Inoue, JI, Matsuda, Z

Antimicrob. Agents Chemother. 2016
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