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Review

Type II transmembrane serine proteases as potential target for anti-influenza drug discovery

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Pages 1139-1152 | Received 28 Feb 2017, Accepted 24 Aug 2017, Published online: 05 Sep 2017

References

  • Taubenberger JK, Morens DM. The pathology of influenza virus infections. Annu Rev Pathol. 2008;3:499–522.
  • Thompson WW, Shay DK, Weintraub E, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA. 2003;289(2):179–186.
  • Smith RD, Keogh-Brown MR, Barnett T, et al. The economy-wide impact of pandemic influenza on the UK: a computable general equilibrium modelling experiment. BMJ. 2009;339:b4571.
  • Freemantle N, Shallcross LJ, Kyte D, et al. Oseltamivir: the real world data. BMJ. 2014;348:g2371.
  • van der Vries E, Stelma FF, Boucher CA. Emergence of a multidrug-resistant pandemic influenza A (H1N1) virus. N Engl J Med. 2010;363(14):1381–1382.
  • Viboud C, Simonsen L. Global mortality of 2009 pandemic influenza A H1N1. Lancet Infect Dis. 2012;12(9):651–653.
  • Bouvier NM, Palese P. The biology of influenza viruses. Vaccine. 2008;26(Suppl 4):D49–D53.
  • Adams MJ, Lefkowitz EJ, King AMQ, et al. Changes to taxonomy and the International Code of Virus Classification and Nomenclature ratified by the International Committee on Taxonomy of Viruses (2017). Arch Virol. 2017;162(8):2505–2538.
  • Smith GJ, Vijaykrishna D, Bahl J, et al. Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic. Nature. 2009;459(7250):1122–1125.
  • Wikramaratna PS, Sandeman M, Recker M, et al. The antigenic evolution of influenza: drift or thrift? Philos Trans R Soc Lond B Biol Sci. 2013;368(1614):20120200.
  • Garten RJ, Davis CT, Russell CA, et al. Antigenic and genetic characteristics of swine-origin 2009 A(H1N1) influenza viruses circulating in humans. Science. 2009;325(5937):197–201.
  • Perdue ML, Arnold F, Li S, et al. The future of cell culture-based influenza vaccine production. Expert Rev Vaccines. 2011;10(8):1183–1194.
  • Kallewaard NL, Corti D, Collins PJ, et al. Structure and function analysis of an antibody recognizing all influenza A subtypes. Cell. 2016;166(3):596–608.
  • Marjuki H, Mishin VP, Chai N, et al. Human monoclonal antibody 81.39a effectively neutralizes emerging influenza A viruses of group 1 and 2 hemagglutinins. J Virol. 2016;90(23):10446–10458.
  • Jang YH, Seong BL. Options and obstacles for designing a universal influenza vaccine. Viruses. 2014;6(8):3159–3180.
  • Pica N, Palese P. Toward a universal influenza virus vaccine: prospects and challenges. Annu Rev Med. 2013;64:189–202.
  • Khurana S, Loving CL, Manischewitz J, et al. Vaccine-induced anti-HA2 antibodies promote virus fusion and enhance influenza virus respiratory disease. Sci Transl Med. 2013;5(200):200ra114.
  • Crowe JE Jr. Universal flu vaccines: primum non nocere. Sci Transl Med. 2013;5(200):200fs34.
  • Soema PC, Kompier R, Amorij J-P, et al. Current and next generation influenza vaccines: formulation and production strategies. Eur J Pharm Biopharm. 2015;94:251–263.
  • Wong S-S, Webby RJ. Traditional and new influenza vaccines. Clin Microbiol Rev. 2013;26(3):476–492.
  • Bright RA, Shay DK, Shu B, et al. Adamantane resistance among influenza A viruses isolated early during the 2005–2006 influenza season in the United States. JAMA. 2006;295(8):891–894.
  • Song M-S, Marathe BM, Kumar G, et al. Unique determinants of neuraminidase inhibitor resistance among N3, N7, and N9 avian influenza viruses. J Virol. 2015;89(21):10891–10900.
  • Hai R, Schmolke M, Leyva-Grado VH, et al. Influenza A(H7N9) virus gains neuraminidase inhibitor resistance without loss of in vivo virulence or transmissibility. Nat Commun. 2013;4:2854.
  • Nguyen HT, Fry AM, Gubareva LV. Neuraminidase inhibitor resistance in influenza viruses and laboratory testing methods. Antivir Ther. 2012;17(1 Pt B):159–173.
  • Shin W-J, Seong BL. Recent advances in pharmacophore modeling and its application to anti-influenza drug discovery. Expert Opin Drug Discov. 2013;8(4):411–426.
  • Engel DA. The influenza virus NS1 protein as a therapeutic target. Antiviral Res. 2013;99(3):409–416.
  • Chokki M, Yamamura S, Eguchi H, et al. Human airway trypsin-like protease increases mucin gene expression in airway epithelial cells. Am J Respir Cell Mol Biol. 2004;30(4):470–478.
  • Shaw ML. The host interactome of influenza virus presents new potential targets for antiviral drugs. Rev Med Virol. 2011;21(6):358–369.
  • Jorba N, Juarez S, Torreira E, et al. Analysis of the interaction of influenza virus polymerase complex with human cell factors. Proteomics. 2008;8(10):2077–2088.
  • Tafforeau L, Chantier T, Pradezynski F, et al. Generation and comprehensive analysis of an influenza virus polymerase cellular interaction network. J Virol. 2011;85(24):13010–13018.
  • Shapira SD, Gat-Viks I, Shum BO, et al. A physical and regulatory map of host-influenza interactions reveals pathways in H1N1 infection. Cell. 2009;139(7):1255–1267.
  • Triana-Baltzer GB, Sanders RL, Hedlund M, et al. Phenotypic and genotypic characterization of influenza virus mutants selected with the sialidase fusion protein DAS181. J Antimicrob Chemother. 2011;66(1):15–28.
  • Edinger TO, Pohl MO, Stertz S. Entry of influenza A virus: host factors and antiviral targets. J Gen Virol. 2014;95(Pt 2):263–277.
  • Marjuki H, Mishin VP, Chesnokov AP, et al. An investigational antiviral drug, DAS181, effectively inhibits replication of zoonotic influenza A virus subtype H7N9 and protects mice from lethality. J Infect Dis. 2014;210(3):435–440.
  • Moss RB, Hansen C, Sanders RL, et al. A phase II study of DAS181, a novel host directed antiviral for the treatment of influenza infection. J Infect Dis. 2012;206(12):1844–1851.
  • Taubenberger JK. Influenza virus hemagglutinin cleavage into HA1, HA2: no laughing matter. Proc Natl Acad Sci U S A. 1998;95(17):9713–9715.
  • Grove J, Marsh M. The cell biology of receptor-mediated virus entry. J Cell Biol. 2011;195(7):1071–1082.
  • Bertram S, Glowacka I, Steffen I, et al. Novel insights into proteolytic cleavage of influenza virus hemagglutinin. Rev Med Virol. 2010;20(5):298–310.
  • Böttcher-Friebertshäuser E, Garten W, Matrosovich M, et al. The hemagglutinin: a determinant of pathogenicity. Curr Top Microbiol Immunol. 2014;385:3–34.
  • Wang S, Le TQ, Kurihara N, et al. Influenza virus-cytokine-protease cycle in the pathogenesis of vascular hyperpermeability in severe influenza. J Infect Dis. 2010;202(7):991–1001.
  • Klenk HD, Rott R, Orlich M, et al. Activation of influenza A viruses by trypsin treatment. Virology. 1975;68(2):426–439.
  • Kido H, Yokogoshi Y, Sakai K, et al. Isolation and characterization of a novel trypsin-like protease found in rat bronchiolar epithelial Clara cells. A possible activator of the viral fusion glycoprotein. J Biol Chem. 1992;267(19):13573–13579.
  • Murakami M, Towatari T, Ohuchi M, et al. Mini-plasmin found in the epithelial cells of bronchioles triggers infection by broad-spectrum influenza A viruses and Sendai virus. Eur J Biochem. 2001;268(10):2847–2855.
  • Hooper JD, Clements JA, Quigley JP, et al. Type II transmembrane serine proteases. Insights into an emerging class of cell surface proteolytic enzymes. J Biol Chem. 2001;276(2):857–860.
  • Bugge TH, Antalis TM, Wu Q. Type II transmembrane serine proteases. J Biol Chem. 2009;284(35):23177–23181.
  • Yamaya M, Shimotai Y. Serine proteases and their inhibitors in human airway epithelial cells: effects on influenza virus replication and airway serine proteases and their inhibitors in human airway epithelial cells: effects on influenza virus replication and airway inflammation. Clin Microbiol. 2016;5(2).
  • Kühn N, Bergmann S, Kösterke N, et al. The proteolytic activation of (H3N2) influenza A virus hemagglutinin is facilitated by different type II transmembrane serine proteases. J Virol. 2016;90(9):4298–4307.
  • Meyer D, Sielaff F, Hammami M, et al. Identification of the first synthetic inhibitors of the type II transmembrane serine protease TMPRSS2 suitable for inhibition of influenza virus activation. Biochem J. 2013;452(2):331–343.
  • Okumura Y, Takahashi E, Yano M, et al. Novel type II transmembrane serine proteases, MSPL and TMPRSS13, proteolytically activate membrane fusion activity of the hemagglutinin of highly pathogenic avian influenza viruses and induce their multicycle replication. J Virol. 2010;84(10):5089–5096.
  • Böttcher-Friebertshäuser E, Freuer C, Sielaff F, et al. Cleavage of influenza virus hemagglutinin by airway proteases TMPRSS2 and HAT differs in subcellular localization and susceptibility to protease inhibitors. J Virol. 2010;84(11):5605–5614.
  • Choi S-Y, Bertram S, Glowacka I, et al. Type II transmembrane serine proteases in cancer and viral infections. Trends Mol Med. 2009;15(7):303–312.
  • Böttcher E, Freuer C, Steinmetzer T, et al. MDCK cells that express proteases TMPRSS2 and HAT provide a cell system to propagate influenza viruses in the absence of trypsin and to study cleavage of HA and its inhibition. Vaccine. 2009;27(45):6324–6329.
  • Hatesuer B, Bertram S, Mehnert N, et al. Tmprss2 is essential for influenza H1N1 virus pathogenesis in mice. PLoS Pathog. 2013;9(12):e1003774.
  • Hedstrom L. Serine protease mechanism and specificity. Chem Rev. 2002;102(12):4501–4524.
  • Dodson G, Wlodawer A. Catalytic triads and their relatives. Trends Biochem Sci. 1998;23(9):347–352.
  • Rawlings ND, Waller M, Barrett AJ, et al. MEROPS: the database of proteolytic enzymes, their substrates and inhibitors. Nucleic Acids Res. 2014;42(Database issue):D503–D509.
  • Pham CT. Neutrophil serine proteases: specific regulators of inflammation. Nat Rev Immunol. 2006;6(7):541–550.
  • Zheng XL, Kitamoto Y, Sadler JE. Enteropeptidase, a type II transmembrane serine protease. Front Biosci (Elite Ed). 2009;1:242–249.
  • Walsh PN, Ahmad SS. Proteases in blood clotting. Essays Biochem. 2002;38:95–111.
  • Le Magueresse-Battistoni B. Serine proteases and serine protease inhibitors in testicular physiology: the plasminogen activation system. Reproduction. 2007;134(6):721–729.
  • Murray AS, Varela FA, List K. Type II transmembrane serine proteases as potential targets for cancer therapy. Biol Chem. 2016;397(9):815–826.
  • List K, Bugge TH. Physiological and pathological functions of type II transmembrane serine proteases: lessons from transgenic mouse models and human disease-associated mutations. In: Edwards D, Høyer-Hansen G, Blasi F, et al., editors. The cancer degradome: proteases and cancer biology. New York (NY): Springer New York; 2008. p. 259–279.
  • Kido H, Beppu Y, Sakai K, et al. Molecular basis of proteolytic activation of Sendai virus infection and the defensive compounds for infection. Biol Chem. 1997;378(3–4):255–263.
  • Böttcher E, Matrosovich T, Beyerle M, et al. Proteolytic activation of influenza viruses by serine proteases TMPRSS2 and HAT from human airway epithelium. J Virol. 2006;80(19):9896–9898.
  • Antalis TM, Buzza MS, Hodge KM, et al. The cutting edge: membrane-anchored serine protease activities in the pericellular microenvironment. Biochem J. 2010;428(3):325–346.
  • Garten W, Braden C, Arendt A, et al. Influenza virus activating host proteases: identification, localization and inhibitors as potential therapeutics. Eur J Cell Biol. 2015;94(7–9):375–383.
  • Antalis TM, Conway GD, Peroutka RJ, et al. Membrane-anchored proteases in endothelial cell biology. Curr Opin Hematol. 2016;23(3):243–252.
  • Kitamoto Y, Veile RA, Donis-Keller H, et al. cDNA sequence and chromosomal localization of human enterokinase, the proteolytic activator of trypsinogen. Biochemistry. 1995;34(14):4562–4568.
  • Haworth JC, Gourley B, Hadorn B, et al. Malabsorption and growth failure due to intestinal enterokinase deficiency. J Pediatr. 1971;78(3):481–490.
  • Holzinger A, Maier EM, Bück C, et al. Mutations in the proenteropeptidase gene are the molecular cause of congenital enteropeptidase deficiency. Am J Hum Genet. 2002;70(1):20–25.
  • Yan W, Sheng N, Seto M, et al. Corin, a mosaic transmembrane serine protease encoded by a novel cDNA from human heart. J Biol Chem. 1999;274(21):14926–14935.
  • Wang W, Liao X, Fukuda K, et al. Corin variant associated with hypertension and cardiac hypertrophy exhibits impaired zymogen activation and natriuretic peptide processing activity. Circ Res. 2008;103(5):502–508.
  • Dries DL, Victor RG, Rame JE, et al. Corin gene minor allele defined by 2 missense mutations is common in blacks and associated with high blood pressure and hypertension. Circulation. 2005;112(16):2403–2410.
  • Rame JE, Tam SW, McNamara D, et al. Dysfunctional corin i555(p568) allele is associated with impaired brain natriuretic peptide processing and adverse outcomes in blacks with systolic heart failure: results from the genetic risk assessment in heart failure substudy. Circ Heart Fail. 2009;2(6):541–548.
  • Rame JE, Drazner MH, Post W, et al. Corin I555(P568) allele is associated with enhanced cardiac hypertrophic response to increased systemic afterload. Hypertension. 2007;49(4):857–864.
  • Yasuoka S, Ohnishi T, Kawano S, et al. Purification, characterization, and localization of a novel trypsin-like protease found in the human airway. Am J Respir Cell Mol Biol. 1997;16(3):300–308.
  • Yamaoka K, Masuda K, Ogawa H, et al. Cloning and characterization of the cDNA for human airway trypsin-like protease. J Biol Chem. 1998;273(19):11895–11901.
  • Sales KU, Hobson JP, Wagenaar-Miller R, et al. Expression and genetic loss of function analysis of the HAT/DESC cluster proteases TMPRSS11A and HAT. PLoS One. 2011;6(8):e23261.
  • Yoshinaga S, Nakahori Y, Yasuoka S. Fibrinogenolytic activity of a novel trypsin-like enzyme found in human airway. J Med Invest. 1998;45(1–4):77–86.
  • Matsushima R, Takahashi A, Nakaya Y, et al. Human airway trypsin-like protease stimulates human bronchial fibroblast proliferation in a protease-activated receptor-2-dependent pathway. Am J Physiol Lung Cell Mol Physiol. 2006;290(2):L385–L395.
  • Kim TS, Heinlein C, Hackman RC, et al. Phenotypic analysis of mice lacking the Tmprss2-encoded protease. Mol Cell Biol. 2006;26(3):965–975.
  • Sakai K, Ami Y, Nakajima N, et al. TMPRSS2 independency for haemagglutinin cleavage in vivo differentiates influenza B virus from influenza A virus. Sci Rep. 2016;6:29430.
  • Kakisaka M, Sasaki Y, Yamada K, et al. A novel antiviral target structure involved in the RNA binding, dimerization, and nuclear export functions of the influenza A virus nucleoprotein. PLoS Pathog. 2015;11(7):e1005062.
  • Lejal N, Tarus B, Bouguyon E, et al. Structure-based discovery of the novel antiviral properties of naproxen against the nucleoprotein of influenza A virus. Antimicrob Agents Chemother. 2013;57(5):2231–2242.
  • Hayden FG. Newer influenza antivirals, biotherapeutics and combinations. Influenza Other Respir Viruses. 2013;7(Suppl 1):63–75.
  • Naesens L, Stevaert A, Vanderlinden E. Antiviral therapies on the horizon for influenza. Curr Opin Pharmacol. 2016;30:106–115.
  • Haffizulla J, Hartman A, Hoppers M, et al. Effect of nitazoxanide in adults and adolescents with acute uncomplicated influenza: a double-blind, randomised, placebo-controlled, phase 2b/3 trial. Lancet Infect Dis. 2014;14(7):609–618.
  • Rossignol JF, La Frazia S, Chiappa L, et al. Thiazolides, a new class of anti-influenza molecules targeting viral hemagglutinin at the post-translational level. J Biol Chem. 2009;284(43):29798–29808.
  • Furuta Y, Gowen BB, Takahashi K, et al. Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antiviral Res. 2013;100(2):446–454.
  • Byrn RA, Jones SM, Bennett HB, et al. Preclinical activity of VX-787, a first-in-class, orally bioavailable inhibitor of the influenza virus polymerase PB2 subunit. Antimicrob Agents Chemother. 2015;59(3):1569–1582.
  • Kao RY, Yang D, Lau L-S, et al. Identification of influenza A nucleoprotein as an antiviral target. Nat Biotechnol. 2010;28(6):600–605.
  • Pang B, Cheung NN, Zhang W, et al. Structural characterization of H1N1 nucleoprotein-nucleozin binding sites. Sci Rep. 2016;6:29684.
  • Gerritz SW, Cianci C, Kim S, et al. Inhibition of influenza virus replication via small molecules that induce the formation of higher-order nucleoprotein oligomers. Proc Natl Acad Sci U S A. 2011;108(37):15366–15371.
  • Barré O, Dufour A, Eckhard U, et al. Cleavage specificity analysis of six type II transmembrane serine proteases (TTSPs) using PICS with proteome-derived peptide libraries. PLoS One. 2014;9(9):e105984.
  • Szabo R, Bugge TH. Membrane-anchored serine proteases in vertebrate cell and developmental biology. Annu Rev Cell Dev Biol. 2011;27:213–235.
  • Ohler A, Becker-Pauly C. TMPRSS4 is a type II transmembrane serine protease involved in cancer and viral infections. Biol Chem. 2012;393(9):907–914.
  • Chan JC, Knudson O, Wu F, et al. Hypertension in mice lacking the proatrial natriuretic peptide convertase corin. Proc Natl Acad Sci U S A. 2005;102(3):785–790.
  • Zhirnov OP, Ikizler MR, Wright PF. Cleavage of influenza a virus hemagglutinin in human respiratory epithelium is cell associated and sensitive to exogenous antiproteases. J Virol. 2002;76(17):8682–8689.
  • Steinhauer DA. Role of hemagglutinin cleavage for the pathogenicity of influenza virus. Virology. 1999;258(1):1–20.
  • Lu X, Shi Y, Gao F, et al. Insights into avian influenza virus pathogenicity: the hemagglutinin precursor HA0 of subtype H16 has an alpha-helix structure in its cleavage site with inefficient HA1/HA2 cleavage. J Virol. 2012;86(23):12861–12870.
  • Chen J, Lee KH, Steinhauer DA, et al. Structure of the hemagglutinin precursor cleavage site, a determinant of influenza pathogenicity and the origin of the labile conformation. Cell. 1998;95(3):409–417.
  • Evnin LB, Vasquez JR, Craik CS. Substrate specificity of trypsin investigated by using a genetic selection. Proc Natl Acad Sci U S A. 1990;87(17):6659–6663.
  • Lazarowitz SG, Choppin PW. Enhancement of the infectivity of influenza A and B viruses by proteolytic cleavage of the hemagglutinin polypeptide. Virology. 1975;68(2):440–454.
  • Huai Q, Mazar AP, Kuo A, et al. Structure of human urokinase plasminogen activator in complex with its receptor. Science. 2006;311(5761):656–659.
  • Blouse GE, Bøtkjær KA, Deryugina E, et al. A novel mode of intervention with serine protease activity: targeting zymogen activation. J Biol Chem. 2009;284(7):4647–4657.
  • Hamilton BS, Whittaker GR. Cleavage activation of human-adapted influenza virus subtypes by kallikrein-related peptidases 5 and 12. J Biol Chem. 2013;288(24):17399–17407.
  • Chaipan C, Kobasa D, Bertram S, et al. Proteolytic activation of the 1918 influenza virus hemagglutinin. J Virol. 2009;83(7):3200–3211.
  • Hamilton BS, Gludish DW, Whittaker GR. Cleavage activation of the human-adapted influenza virus subtypes by matriptase reveals both subtype and strain specificities. J Virol. 2012;86(19):10579–10586.
  • Zhirnov OP, Ovcharenko AV, Bukrinskaya AG. Myxovirus replication in chicken embryos can be suppressed by aprotinin due to the blockage of viral glycoprotein cleavage. J Gen Virol. 1985;66(7):1633–1638.
  • Cheng Z, Zhou J, To KK, et al. Identification of TMPRSS2 as a susceptibility gene for severe 2009 pandemic A(H1N1) influenza and A(H7N9) influenza. J Infect Dis. 2015;212(8):1214–1221.
  • Stieneke-Gröber A, Vey M, Angliker H, et al. Influenza virus hemagglutinin with multibasic cleavage site is activated by furin, a subtilisin-like endoprotease. Embo J. 1992;11(7):2407–2414.
  • Suguitan AL Jr, Matsuoka Y, Lau Y-F, et al. The multibasic cleavage site of the hemagglutinin of highly pathogenic A/Vietnam/1203/2004 (H5N1) avian influenza virus acts as a virulence factor in a host-specific manner in mammals. J Virol. 2012;86(5):2706–2714.
  • Horimoto T, Nakayama K, Smeekens SP, et al. Proprotein-processing endoproteases PC6 and furin both activate hemagglutinin of virulent avian influenza viruses. J Virol. 1994;68(9):6074–6078.
  • Kido H, Okumura Y. Mspl/Tmprss13. Front Biosci. 2008;13:754–758.
  • Baron J, Tarnow C, Mayoli-Nüssle D, et al. Matriptase, HAT, and TMPRSS2 activate the hemagglutinin of H9N2 influenza A viruses. J Virol. 2013;87(3):1811–1820.
  • Zhirnov OP, Ovcharenko AV, Bukrinskaya AG. Protective effect of protease inhibitors in influenza virus infected animals. Arch Virol. 1982;73(3–4):263–272.
  • Zhirnov OP, Ovcharenko AV, Bukrinskaya AG. Suppression of influenza virus replication in infected mice by protease inhibitors. J Gen Virol. 1984;65(1):191–196.
  • Bahgat MM, Błazejewska P, Schughart K. Inhibition of lung serine proteases in mice: a potentially new approach to control influenza infection. Virol J. 2011;8:27.
  • Lee MG, Kim KH, Park KY, et al. Evaluation of anti-influenza effects of camostat in mice infected with non-adapted human influenza viruses. Arch Virol. 1996;141(10):1979–1989.
  • Hosoya M, Shigeta S, Ishii T, et al. Comparative inhibitory effects of various nucleoside and nonnucleoside analogues on replication of influenza virus types A and B in vitro and in ovo. J Infect Dis. 1993;168(3):641–646.
  • Wysocka M, Spichalska B, Lesner A, et al. Substrate specificity and inhibitory study of human airway trypsin-like protease. Bioorg Med Chem. 2010;18(15):5504–5509.
  • Zmora P, Blazejewska P, Moldenhauer A-S, et al. DESC1 and MSPL activate influenza A viruses and emerging coronaviruses for host cell entry. J Virol. 2014;88(20):12087–12097.
  • Garten W, Stieneke A, Shaw E, et al. Inhibition of proteolytic activation of influenza virus hemagglutinin by specific peptidyl chloroalkyl ketones. Virology. 1989;172(1):25–31.
  • Beppu Y, Imamura Y, Tashiro M, et al. Human mucus protease inhibitor in airway fluids is a potential defensive compound against infection with influenza A and Sendai viruses. J Bioch. 1997;121(2):309–316.
  • Kyrieleis OJ, Huber R, Ong E, et al. Crystal structure of the catalytic domain of DESC1, a new member of the type II transmembrane serine proteinase family. Febs J. 2007;274(8):2148–2160.
  • Sielaff F, Böttcher-Friebertshäuser E, Meyer D, et al. Development of substrate analogue inhibitors for the human airway trypsin-like protease HAT. Bioorg Med Chem Lett. 2011;21(16):4860–4864.
  • Sisay MT, Steinmetzer T, Stirnberg M, et al. Identification of the first low-molecular-weight inhibitors of matriptase-2. J Med Chem. 2010;53(15):5523–5535.
  • Hellstern P, Stürzebecher U, Wuchold B, et al. Preservation of in vitro function of platelets stored in the presence of a synthetic dual inhibitor of factor Xa and thrombin. J Thromb Haemost. 2007;5(10):2119–2126.
  • Böttcher-Friebertshäuser E, Lu Y, Meyer D, et al. Hemagglutinin activating host cell proteases provide promising drug targets for the treatment of influenza A and B virus infections. Vaccine. 2012;30(51):7374–7380.
  • Yamaya M, Shimotai Y, Hatachi Y, et al. The serine protease inhibitor camostat inhibits influenza virus replication and cytokine production in primary cultures of human tracheal epithelial cells. Pulm Pharmacol Ther. 2015;33:66–74.
  • Buzza MS, Johnson TA, Conway GD, et al. Inflammatory cytokines down-regulate the barrier-protective prostasin-matriptase proteolytic cascade early in experimental colitis. J Biol Chem. 2017;292(26):10801–10812.
  • Kaplan BS, Russier M, Jeevan T, et al. Novel highly pathogenic avian A(H5N2) and A(H5N8) influenza viruses of clade 2.3.4.4 from North America have limited capacity for replication and transmission in mammals. mSphere. 2016;1(2).
  • Zhirnov OP, Matrosovich TY, Matrosovich MN, et al. Aprotinin, a protease inhibitor, suppresses proteolytic activation of pandemic H1N1v influenza virus. Antivir Chem Chemother. 2011;21(4):169–174.
  • Zhirnov OP, Kirzhner LS, Ovcharenko AV, et al. [Clinical effectiveness of aprotinin aerosol in influenza and parainfluenza]. Vestnik Rossiiskoi akademii meditsinskikh nauk/Rossiiskaia akademiia meditsinskikh nauk. 1996;(5):26–31.
  • Simmons G, Zmora P, Gierer S, et al. Proteolytic activation of the SARS-coronavirus spike protein: cutting enzymes at the cutting edge of antiviral research. Antiviral Res. 2013;100(3):605–614.
  • Krzyzaniak MA, Zumstein MT, Gerez JA, et al. Host cell entry of respiratory syncytial virus involves macropinocytosis followed by proteolytic activation of the F protein. PLoS Pathog. 2013;9(4):e1003309.
  • Shirato K, Kawase M, Matsuyama S. Middle east respiratory syndrome coronavirus infection mediated by the transmembrane serine protease TMPRSS2. J Virol. 2013;87(23):12552–12561.
  • Sanjuán R, Nebot MR, Chirico N, et al. Viral mutation rates. J Virol. 2010;84(19):9733–9748.
  • Phougat N, Khatri S, Singh A, et al. Combination therapy: the propitious rationale for drug development. Comb Chem High Throughput Screen. 2014;17(1):53–67.
  • Johnson LB, Saravolatz LD. The quad pill, a once-daily combination therapy for HIV infection. Clin Infect Dis. 2014;58(1):93–98.
  • Steinmetzer T, Schweinitz A, Stürzebecher A, et al. Secondary amides of sulfonylated 3-amidinophenylalanine. new potent and selective inhibitors of matriptase. J Med Chem. 2006;49(14):4116–4126.

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