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Book ; Online ; E-Book: Activation of viruses by host proteases

Böttcher-Friebertshäuser, Eva / Garten, Wolfgang / Klenk, Hans-Dieter

2018

Author's details	Eva Böttcher-Friebertshäuser, Wolfgang Garten, Hans-Dieter Klenk editors
Language	English
Size	1 Online-Ressource (x, 335 Seiten), Illustrationen, Diagramme
Publisher	Springer
Publishing place	Cham
Publishing country	Switzerland
Document type	Book ; Online ; E-Book
Remark	Zugriff für angemeldete ZB MED-Nutzerinnen und -Nutzer
HBZ-ID	HT019729608
ISBN	978-3-319-75474-1 ; 9783319754734 ; 3-319-75474-2 ; 3319754734
DOI	10.1007/978-3-319-75474-1
Database	ZB MED Catalogue: Medicine, Health, Nutrition, Environment, Agriculture

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Article ; Online: The role of influenza-A virus and coronavirus viral glycoprotein cleavage in host adaptation.

Heindl, Miriam R / Böttcher-Friebertshäuser, Eva

Current opinion in virology

2023 Volume 58, Page(s) 101303

Abstract: While receptor binding is well recognized as a factor in influenza-A virus (IAV) and coronavirus (CoV) host adaptation, the role of viral glycoprotein cleavage has not been studied in detail so far. Interestingly, recent studies suggest that host species ...

Abstract	While receptor binding is well recognized as a factor in influenza-A virus (IAV) and coronavirus (CoV) host adaptation, the role of viral glycoprotein cleavage has not been studied in detail so far. Interestingly, recent studies suggest that host species may differ in their protease repertoire available for cleavage. Furthermore, it was shown for certain bat-derived CoVs that proteolytic activation provides a critical barrier to infect human cells. Understanding the role of glycoprotein cleavage in different species and how IAV and CoVs adapt to a new protease repertoire may allow evaluating the zoonotic potential and risk posed by these viruses. Here, we summarize the current knowledge on the emergence of a multibasic cleavage site (CS) in the glycoproteins of IAVs and CoVs in different host species. Additionally, we discuss the role of transmembrane serine protease 2 (TMPRSS2) in virus activation and entry and a role of neuropilin-1 in acquisition of a multibasic CS in different hosts.
MeSH term(s)	Humans ; Coronavirus ; Coronavirus Infections ; Host Adaptation ; Influenza A virus/physiology ; Influenza, Human ; Peptide Hydrolases ; Virus Internalization ; Glycoproteins ; Viral Proteins/metabolism
Chemical Substances	Peptide Hydrolases (EC 3.4.-) ; Glycoproteins ; Viral Proteins
Language	English
Publishing date	2023-01-18
Publishing country	Netherlands
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2611378-8
ISSN	1879-6265 ; 1879-6257
ISSN (online)	1879-6265
ISSN	1879-6257
DOI	10.1016/j.coviro.2023.101303
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Article ; Online: TMPRSS2, a novel host-directed drug target against SARS-CoV-2.

Keller, Christian / Böttcher-Friebertshäuser, Eva / Lohoff, Michael

Signal transduction and targeted therapy

2022 Volume 7, Issue 1, Page(s) 251

MeSH term(s)	COVID-19/drug therapy ; Humans ; SARS-CoV-2 ; Serine Endopeptidases/genetics
Chemical Substances	Serine Endopeptidases (EC 3.4.21.-) ; TMPRSS2 protein, human (EC 3.4.21.-)
Language	English
Publishing date	2022-07-23
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	2886872-9
ISSN	2059-3635 ; 2095-9907
ISSN (online)	2059-3635
ISSN	2095-9907
DOI	10.1038/s41392-022-01084-x
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Article ; Online: pH inactivation of SARS-CoV-2 and SARS-CoV in virus spiked protein A eluates from a mAb purification process.

Limburg, Hannah / Schwerdtner, Marie / Wilson, Eileen / Roth, Bernhard / Cassart, Jean-Pol / Werner, Anke-Dorothee / Harbig, Anne / Böttcher-Friebertshäuser, Eva / Stokes, Anne

Biologicals : journal of the International Association of Biological Standardization

2024 Volume 86, Page(s) 101753

Abstract: Biopharmaceutical manufacturing processes may include a low pH treatment step as a means of inactivating enveloped viruses. Small scale virus clearance studies are routinely performed using model enveloped viruses such as murine leukemia virus to assess ... ...

Abstract	Biopharmaceutical manufacturing processes may include a low pH treatment step as a means of inactivating enveloped viruses. Small scale virus clearance studies are routinely performed using model enveloped viruses such as murine leukemia virus to assess inactivation at the pH range used in the downstream manufacturing process. Further, as a means of bioburden reduction, chromatography resins may be cleaned and stored using sodium hydroxide and this can also inactivate viruses. The susceptibility of SARS-CoV-2 and SARS-CoV to low pH conditions using protein A eluate derived material from a monoclonal antibody production process as well as high pH cleaning conditions was addressed. SARS-CoV-2 was effectively inactivated at pH 3.0, moderately inactivated at pH 3.4, but not inactivated at pH 3.8. Low pH was less effective at inactivating SARS-CoV. Both viruses were inactivated at a high pH of ca.13.4. These studies provide important information regarding the effectiveness of viral clearance and inactivation steps of novel coronaviruses when compared to other enveloped viruses.
Language	English
Publishing date	2024-03-14
Publishing country	England
Document type	Journal Article
ZDB-ID	1017370-5
ISSN	1095-8320 ; 1045-1056
ISSN (online)	1095-8320
ISSN	1045-1056
DOI	10.1016/j.biologicals.2024.101753
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Article ; Online: Membrane-Anchored Serine Proteases: Host Cell Factors in Proteolytic Activation of Viral Glycoproteins

Böttcher-Friebertshäuser, Eva

Activation of Viruses by Host Proteases

Abstract: Over one third of all known proteolytic enzymes are serine proteases. Among these, the trypsin-like serine proteases comprise one of the best characterized subfamilies due to their essential roles in blood coagulation, food digestion, fibrinolysis, or ... ...

Abstract	Over one third of all known proteolytic enzymes are serine proteases. Among these, the trypsin-like serine proteases comprise one of the best characterized subfamilies due to their essential roles in blood coagulation, food digestion, fibrinolysis, or immunity. Trypsin-like serine proteases possess primary substrate specificity for basic amino acids. Most of the well-characterized trypsin-like proteases such as trypsin, plasmin, or urokinase are soluble proteases that are secreted into the extracellular environment. At the turn of the millennium, a number of novel trypsin-like serine proteases have been identified that are anchored in the cell membrane, either by a transmembrane domain at the N- or C-terminus or via a glycosylphosphatidylinositol (GPI) linkage. Meanwhile more than 20 membrane-anchored serine proteases (MASPs) have been identified in human and mouse, and some of them have emerged as key regulators of mammalian development and homeostasis. Thus, the MASP corin and TMPRSS6/matriptase-2 have been demonstrated to be the activators of the atrial natriuretic peptide (ANP) and key regulator of hepcidin expression, respectively. Furthermore, MASPs have been recognized as host cell factors activating respiratory viruses including influenza virus as well as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) coronaviruses. In particular, transmembrane protease serine S1 member 2 (TMPRSS2) has been shown to be essential for proteolytic activation and consequently spread and pathogenesis of a number of influenza A viruses in mice and as a factor associated with severe influenza virus infection in humans. This review gives an overview on the physiological functions of the fascinating and rapidly evolving group of MASPs and a summary of the current knowledge on their role in proteolytic activation of viral fusion proteins.
Keywords	covid19
Publisher	PMC
Document type	Article ; Online
DOI	10.1007/978-3-319-75474-1_8
Database	COVID19

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Article: TMPRSS2 Impacts Cytokine Expression in Murine Dendritic Cells.

Gunne, Sandra / Schwerdtner, Marie / Henke, Marina / Schneider, Ann-Kathrin / Keutmann, Lucas / Böttcher-Friebertshäuser, Eva / Schiffmann, Susanne

Biomedicines

2023 Volume 11, Issue 2

Abstract: Background: The transmembrane protease serine 2 (TMPRSS2) proteolytically activates the envelope proteins of several viruses for viral entry via membrane fusion and is therefore an interesting and promising target for the development of broad-spectrum ... ...

Abstract	Background: The transmembrane protease serine 2 (TMPRSS2) proteolytically activates the envelope proteins of several viruses for viral entry via membrane fusion and is therefore an interesting and promising target for the development of broad-spectrum antivirals. However, the use of a host protein as a target may lead to potential side effects, especially on the immune system. We examined the effect of a genetic deletion of Methods: Bone marrow cells from wild-type (WT) and TMPRSS2-deficient mice (TMPRSS2 Results: In cDCs, the lack of TMPRSS2 led to an increase in IL12 and IFNγ in TLR7/8 agonist resiquimod or TLR 9 agonist ODN 1668-activated cells. Only IL-10 was reduced in TMPRSS2 Conclusion: The effect of TMPRSS2 on pDCS and cDCs depends on the activated TLR, and TMPRSS2 seems to affect cytokine release differently in pDCs and cDCs. In cDCs, TMPRSS2 seems to suppress cytokine release, whereas in pDCS TMPRSS2 possibly mediates cytokine release.
Language	English
Publishing date	2023-02-01
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2720867-9
ISSN	2227-9059
ISSN	2227-9059
DOI	10.3390/biomedicines11020419
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Article ; Online: Fragment-Based Design, Synthesis, and Characterization of Aminoisoindole-Derived Furin Inhibitors.

Lange, Roman W / Bloch, Konstantin / Heindl, Miriam Ruth / Wollenhaupt, Jan / Weiss, Manfred S / Brandstetter, Hans / Klebe, Gerhard / Falcone, Franco H / Böttcher-Friebertshäuser, Eva / Dahms, Sven O / Steinmetzer, Torsten

ChemMedChem

2024 Volume 19, Issue 9, Page(s) e202400057

Abstract: A 1H-isoindol-3-amine was identified as suitable P1 group for the proprotein convertase furin using a crystallographic screening with a set of 20 fragments known to occupy the S1 pocket of trypsin-like serine proteases. Its binding mode is very similar ... ...

Abstract	A 1H-isoindol-3-amine was identified as suitable P1 group for the proprotein convertase furin using a crystallographic screening with a set of 20 fragments known to occupy the S1 pocket of trypsin-like serine proteases. Its binding mode is very similar to that observed for the P1 group of benzamidine-derived peptidic furin inhibitors suggesting an aminomethyl substitution of this fragment to obtain a couplable P1 residue for the synthesis of substrate-analogue furin inhibitors. The obtained inhibitors possess a slightly improved picomolar inhibitory potency compared to their benzamidine-derived analogues. The crystal structures of two inhibitors in complex with furin revealed that the new P1 group is perfectly suited for incorporation in peptidic furin inhibitors. Selected inhibitors were tested for antiviral activity against respiratory syncytial virus (RSV) and a furin-dependent influenza A virus (SC35M/H7N7) in A549 human lung cells and demonstrated an efficient inhibition of virus activation and replication at low micromolar or even submicromolar concentrations. First results suggest that the Mas-related G-protein coupled receptor GPCR-X2 could be a potential off-target for certain benzamidine-derived furin inhibitors.
MeSH term(s)	Furin/antagonists & inhibitors ; Furin/metabolism ; Humans ; Drug Design ; Antiviral Agents/pharmacology ; Antiviral Agents/chemical synthesis ; Antiviral Agents/chemistry ; Structure-Activity Relationship ; A549 Cells ; Influenza A virus/drug effects ; Crystallography, X-Ray ; Indoles/pharmacology ; Indoles/chemistry ; Indoles/chemical synthesis ; Molecular Structure ; Models, Molecular ; Respiratory Syncytial Viruses/drug effects ; Dose-Response Relationship, Drug
Chemical Substances	Furin (EC 3.4.21.75) ; Antiviral Agents ; Indoles
Language	English
Publishing date	2024-03-11
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2218496-X
ISSN	1860-7187 ; 1860-7179
ISSN (online)	1860-7187
ISSN	1860-7179
DOI	10.1002/cmdc.202400057
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Zs.A 6280: Show issues

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Article ; Online: ACE2 acts as a novel regulator of TMPRSS2-catalyzed proteolytic activation of influenza A virus in airway cells.

Heindl, Miriam Ruth / Rupp, Anna-Lena / Schwerdtner, Marie / Bestle, Dorothea / Harbig, Anne / De Rocher, Amy / Schmacke, Luna C / Staker, Bart / Steinmetzer, Torsten / Stein, David A / Moulton, Hong M / Böttcher-Friebertshäuser, Eva

Journal of virology

2024 Volume 98, Issue 4, Page(s) e0010224

Abstract: The transmembrane serine protease 2 (TMPRSS2) activates the outer structural proteins of a number of respiratory viruses including influenza A virus (IAV), parainfluenza viruses, and various coronaviruses for membrane fusion. Previous studies showed that ...

Abstract	The transmembrane serine protease 2 (TMPRSS2) activates the outer structural proteins of a number of respiratory viruses including influenza A virus (IAV), parainfluenza viruses, and various coronaviruses for membrane fusion. Previous studies showed that TMPRSS2 interacts with the carboxypeptidase angiotensin-converting enzyme 2 (ACE2), a cell surface protein that serves as an entry receptor for some coronaviruses. Here, by using protease activity assays, we determine that ACE2 increases the enzymatic activity of TMPRSS2 in a non-catalytic manner. Furthermore, we demonstrate that ACE2 knockdown inhibits TMPRSS2-mediated cleavage of IAV hemagglutinin (HA) in Calu-3 human airway cells and suppresses virus titers 100- to 1.000-fold. Transient expression of ACE2 in ACE2-deficient cells increased TMPRSS2-mediated HA cleavage and IAV replication. ACE2 knockdown also reduced titers of MERS-CoV and prevented S cleavage by TMPRSS2 in Calu-3 cells. By contrast, proteolytic activation and multicycle replication of IAV with multibasic HA cleavage site typically cleaved by furin were not affected by ACE2 knockdown. Co-immunoprecipitation analysis revealed that ACE2-TMPRSS2 interaction requires the enzymatic activity of TMPRSS2 and the carboxypeptidase domain of ACE2. Together, our data identify ACE2 as a new co-factor or stabilizer of TMPRSS2 activity and as a novel host cell factor involved in proteolytic activation and spread of IAV in human airway cells. Furthermore, our data indicate that ACE2 is involved in the TMPRSS2-catalyzed activation of additional respiratory viruses including MERS-CoV.IMPORTANCEProteolytic cleavage of viral envelope proteins by host cell proteases is essential for the infectivity of many viruses and relevant proteases provide promising drug targets. The transmembrane serine protease 2 (TMPRSS2) has been identified as a major activating protease of several respiratory viruses, including influenza A virus. TMPRSS2 was previously shown to interact with angiotensin-converting enzyme 2 (ACE2). Here, we report the mechanistic details of this interaction. We demonstrate that ACE2 increases or stabilizes the enzymatic activity of TMPRSS2. Furthermore, we describe ACE2 involvement in TMPRSS2-catalyzed cleavage of the influenza A virus hemagglutinin and MERS-CoV spike protein in human airway cells. These findings expand our knowledge of the activation of respiratory viruses by TMPRSS2 and the host cell factors involved. In addition, our results could help to elucidate a physiological role for TMPRSS2.
MeSH term(s)	Animals ; Dogs ; Humans ; Angiotensin-Converting Enzyme 2/deficiency ; Angiotensin-Converting Enzyme 2/genetics ; Angiotensin-Converting Enzyme 2/metabolism ; Biocatalysis ; Cell Line ; Furin/metabolism ; Hemagglutinin Glycoproteins, Influenza Virus/metabolism ; Influenza A virus/growth & development ; Influenza A virus/metabolism ; Lung/cytology ; Lung/virology ; Middle East Respiratory Syndrome Coronavirus/metabolism ; Protein Binding ; Proteolysis ; Serine Endopeptidases/metabolism ; Spike Glycoprotein, Coronavirus/metabolism ; Virus Internalization ; Virus Replication
Chemical Substances	ACE2 protein, human (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; Furin (EC 3.4.21.75) ; Hemagglutinin Glycoproteins, Influenza Virus ; Serine Endopeptidases (EC 3.4.21.-) ; Spike Glycoprotein, Coronavirus ; TMPRSS2 protein, human (EC 3.4.21.-)
Language	English
Publishing date	2024-03-12
Publishing country	United States
Document type	Journal Article
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/jvi.00102-24
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Article ; Online: Design, synthesis, and characterization of novel fluorogenic substrates of the proprotein convertases furin, PC1/3, PC2, PC5/6, and PC7.

Lam van, Thuy Van / Ivanova, Teodora / Lindberg, Iris / Böttcher-Friebertshäuser, Eva / Steinmetzer, Torsten / Hardes, Kornelia

Analytical biochemistry

2022 Volume 655, Page(s) 114836

Abstract: Proprotein convertases (PCs) are involved in the pathogenesis of various diseases, making them promising drug targets. Most assays for PCs have been performed with few standard substrates, regardless of differences in cleavage efficiencies. Derived from ... ...

Abstract	Proprotein convertases (PCs) are involved in the pathogenesis of various diseases, making them promising drug targets. Most assays for PCs have been performed with few standard substrates, regardless of differences in cleavage efficiencies. Derived from studies on substrate-analogue inhibitors, 11 novel substrates were synthesized and characterized with five PCs. H-Arg-Arg-Tle-Lys-Arg-AMC is the most efficiently cleaved furin substrate based on its k
MeSH term(s)	Amino Acid Sequence ; Carbamates ; Fluorescent Dyes ; Furin ; Oligopeptides ; Proprotein Convertases ; Proteins ; Subtilisins/metabolism
Chemical Substances	Carbamates ; Fluorescent Dyes ; Oligopeptides ; Proteins ; tetrapeptide carbamate ; Proprotein Convertases (EC 3.4.21.-) ; Subtilisins (EC 3.4.21.-) ; Furin (EC 3.4.21.75)
Language	English
Publishing date	2022-08-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1110-1
ISSN	1096-0309 ; 0003-2697
ISSN (online)	1096-0309
ISSN	0003-2697
DOI	10.1016/j.ab.2022.114836
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Article ; Online: TMPRSS2 Impacts Cytokine Expression in Murine Dendritic Cells

Gunne, Sandra / Schwerdtner, Marie / Henke, Marina / Schneider, Ann-Kathrin / Keutmann, Lucas / Böttcher-Friebertshäuser, Eva / Schiffmann, Susanne

2023

Abstract	Background: The transmembrane protease serine 2 (TMPRSS2) proteolytically activates the envelope proteins of several viruses for viral entry via membrane fusion and is therefore an interesting and promising target for the development of broad-spectrum antivirals. However, the use of a host protein as a target may lead to potential side effects, especially on the immune system. We examined the effect of a genetic deletion of TMPRSS2 on dendritic cells. Methods: Bone marrow cells from wild-type (WT) and TMPRSS2-deficient mice (TMPRSS2-/-) were differentiated to plasmacytoid dendritic cells (pDCs) and classical DCs (cDCs) and activated with various toll-like receptor (TLR) agonists. We analyzed the released cytokines and the mRNA expression of chemokine receptors, TLR7, TLR9, IRF7 and TCF4 stimulation. Results: In cDCs, the lack of TMPRSS2 led to an increase in IL12 and IFNγ in TLR7/8 agonist resiquimod or TLR 9 agonist ODN 1668-activated cells. Only IL-10 was reduced in TMPRSS2-/- cells in comparison to WT cells activated with ODN 1668. In resiquimod-activated pDCs, the lack of TMPRSS2 led to a decrease in IL-6, IL-10 and INFγ. ODN 1668 activation led to a reduction in IFNα. The effect on receptor expression in pDCs and cDCs was low. Conclusion: The effect of TMPRSS2 on pDCS and cDCs depends on the activated TLR, and TMPRSS2 seems to affect cytokine release differently in pDCs and cDCs. In cDCs, TMPRSS2 seems to suppress cytokine release, whereas in pDCS TMPRSS2 possibly mediates cytokine release. 11 2
Keywords	cytokine secretion ; dendritic cells ; infection ; TMPRSS2 ; TMPRSS2-knockout mouse
Subject code	616
Language	English
Publishing country	de
Document type	Article ; Online
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