Matriptase, HAT, and TMPRSS2 Activate the Hemagglutinin of H9N2 Influenza A Viruses

Baron, Joanna; Tarnow, Carolin; Mayoli-Nüssle, Deborah; Schilling, Eva; Meyer, Daniela; Hammami, Muhammad M.; Schwalm, Folker; Steinmetzer, Torsten; Guan, Yi; Garten, Wolfgang; Klenk, Hans‐Dieter; Böttcher‐Friebertshäuser, Eva

doi:10.1128/jvi.02320-12

Cited by 126 publications

(142 citation statements)

References 60 publications

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“…Among the suggested human candidates are the kallikreins KLK-5 and KLK-12 [61] or the type II membrane-bound serine proteases HAT (human airway trypsin-like protease or TMPRSS11D) [62], TMPRSS4 [63], DESC1, and MSPL (TMPRSS13) [64]. Despite controversy results, a few H1 subtypes might be also activated by matriptase in addition to TMPRSS2 [65,66]. The contribution of these proteases to HA cleavage in human airways, however, remains to be investigated.…”

Section: Inhibitors Of Ha-activating Host Proteasesmentioning

confidence: 91%

“…Besides TMPRSS2 and HAT, also endogenous matriptase activates certain H9 HAs, which exhibit the di-and tribasic recognition motifs R-S-S-R#G or R-S-R-R#G. When MDCK-II cells, which are known to express significant levels of matriptase, were infected by these H9 influenza strains, the virus growth was suppressed by treatment with the matriptase inhibitor (43) (K i ¼ 3.8 nM) [66].…”

Section: Inhibitors Of Ha-activating Host Proteasesmentioning

confidence: 99%

See 1 more Smart Citation

Strategies for the Development of Influenza Drugs: Basis for New Efficient Combination Therapies

Steinmetzer¹,

Hardes²,

Böttcher‐Friebertshäuser³

et al. 2014

Topics in Medicinal Chemistry

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Only four drugs are approved for the specific treatment of acute influenza infections worldwide. These drugs address either the viral neuraminidase or the M2-channel but suffer from poor efficacy and the rapid emergence of drug resistances. Some additional drugs are launched in few countries, but their efficacy is relatively low and often limited to certain influenza strains. Ideally, new drugs should possess a broad potency against all influenza viruses and be less susceptible to the development of resistances. The propagation cycle of the influenza virus offers many possibilities for the development of new anti-influenza drugs. Various compounds addressing viral targets reached clinical development, from which the most-advanced candidate is the polymerase inhibitor favipiravir. A promising strategy could be also the inhibition of host targets and signaling pathways, e.g., by already approved kinase inhibitors, anti-inflammatory drugs, or immunomodulatory agents. However, the benefit of these agents has to be demonstrated in controlled clinical trials. A broader arsenal of approved drugs will offer the possibility for more efficient combinatorial therapies in the future. The first proof of concept studies for such multiple drug therapies in infected mice revealed beneficial effects. Moreover, this strategy should reduce the rapid emergence of resistant influenza strains.

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Section: Inhibitors Of Ha-activating Host Proteasesmentioning

confidence: 91%

Section: Inhibitors Of Ha-activating Host Proteasesmentioning

confidence: 99%

Strategies for the Development of Influenza Drugs: Basis for New Efficient Combination Therapies

Steinmetzer¹,

Hardes²,

Böttcher‐Friebertshäuser³

et al. 2014

Topics in Medicinal Chemistry

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“…These motifs resemble furin recognition sequences, but they are not cleaved by furin due to a narrow cleavage site loop. These latter types of cleavage sites were found in some H9 virus isolates of LPAIV, which are activated by TMPRSS2, HAT and by matriptase (Garten and Klenk, 2008;Baron et al, 2013;Böttcher-Friebertshäuser et al, 2014). Another unusual cleavage site motif was detected in some highly pathogenic H5 and H7 viruses containing the sequence -K-K-K-R- (Röhm et al, 1996;Senne et al, 1996), which is cleaved by TMPRSS13/MSPL, but not by furin (Okumura et al, 2010).…”

Section: Biosynthesis Structure and Maturation Of Influenza Hamentioning

confidence: 94%

“…They are present in the epithelium of the respiratory tract and promote the propagation of H1, H2 and H3 influenza virus strains as well as of influenza B viruses (Böttcher et al, 2006(Böttcher et al, , 2009Böttcher-Friebertshäuser et al, 2012). The spectrum of HA-activating serine proteases increased with the discovery of matriptase that processes the R-S-S-R↓G and R-S-R-R↓G sequences of some H9 virus strains (Baron et al, 2013;Beaulieu et al, 2013).). Further arginine specific serine protease candidates were shown to cleave HA, such as TMPRSS4, some kallikreins, and DESC1 (Bertram et al, 2010;Hamilton and Whittaker, 2013;Hamilton et al, 2012;Zmora et al, 2014) (Table 1).…”

Section: Identification and Characterization Of Ha-activating Proteasesmentioning

confidence: 96%

Influenza virus activating host proteases: Identification, localization and inhibitors as potential therapeutics

Garten

Braden

Arendt

et al. 2015

European Journal of Cell Biology

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“…Moreover, a strong increase in matriptase expression was observed in inflammatory skin disorders 16 . Recent findings suggest that the host protease matriptase might also be involved in the activation of certain H1 and H9 influenza virus hemagglutinins, which is essential for virus propagation 17,18 . Therefore, matriptase emerged as a potential drug target, especially for the treatment of epithelial tumors.…”

Section: Introductionmentioning

confidence: 99%

Changing the selectivity profile – from substrate analog inhibitors of thrombin and factor Xa to potent matriptase inhibitors

Maiwald

Hammami

Wagner

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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The type II transmembrane serine protease matriptase is a potential target for anticancer therapy and might be involved in cartilage degradation in osteoarthritis or inflammatory skin disorders. Starting from previously described nonspecific thrombin and factor Xa inhibitors we have prepared new noncovalent substrate-analogs with superior potency against matriptase. The most suitable compound 35 (H-D-hTyr-Ala-4-amidinobenzylamide) binds to matriptase with an inhibition constant of 26 nM and has more than 10-fold reduced activity against thrombin and factor Xa. The crystal structure of inhibitor 35 was determined in the surrogate protease trypsin, the obtained complex was used to model the binding mode of inhibitor 35 in the active site of matriptase. The methylene insertion in D-hTyr and D-hPhe increases the flexibility of the P3 side chain compared to their D-Phe analogs, which enables an improved binding of these inhibitors in the well-defined S3/4 pocket of matriptase. Inhibitor 35 can be used for further biochemical studies with matriptase.

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Matriptase, HAT, and TMPRSS2 Activate the Hemagglutinin of H9N2 Influenza A Viruses

Cited by 126 publications

References 60 publications

Strategies for the Development of Influenza Drugs: Basis for New Efficient Combination Therapies

Strategies for the Development of Influenza Drugs: Basis for New Efficient Combination Therapies

Influenza virus activating host proteases: Identification, localization and inhibitors as potential therapeutics

Changing the selectivity profile – from substrate analog inhibitors of thrombin and factor Xa to potent matriptase inhibitors

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