LIVIVO - Search results -

Search results

Result 1 - 10 of total 33

Search options

Book ; Online ; Thesis: Discovery and characterization of protease inhibitors that block SARS-CoV-2 infection

Wettstein, Lukas [Verfasser]

2023

Author's details	Lukas Wettstein
Keywords	Biowissenschaften, Biologie ; Life Science, Biology
Subject code	sg570
Language	English
Publisher	Universität Ulm
Publishing place	Ulm
Document type	Book ; Online ; Thesis
Database	Digital theses on the web

Full text online

Full text

Inter-library loan at ZB MED

Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

Article ; Online: Semen enhances transmitted/founder HIV-1 infection and only marginally reduces antiviral activity of broadly neutralizing antibodies.

von Maltitz, Pascal / Wettstein, Lukas / Weil, Tatjana / Schommers, Philipp / Klein, Florian / Münch, Jan

Journal of virology

2024 Volume 98, Issue 4, Page(s) e0119023

Abstract: Topically applied microbicides may play a critical role in preventing sexual transmission of human immunodeficiency virus type 1 (HIV-1); however, their efficacy can be compromised by amyloid fibrils present in semen, which significantly increase HIV-1 ... ...

Abstract	Topically applied microbicides may play a critical role in preventing sexual transmission of human immunodeficiency virus type 1 (HIV-1); however, their efficacy can be compromised by amyloid fibrils present in semen, which significantly increase HIV-1 infectivity. This phenomenon may have contributed to the failure of most microbicide candidates in clinical settings. Understanding the impact of semen on microbicide effectiveness is thus crucial. In our study, we evaluated the influence of semen on the neutralizing activity of broadly neutralizing antibodies (bNAbs), including PG16, PGT121, 10-1074, 3BNC117, and VRC01, which are potential microbicide candidates. We found that semen enhances infection of HIV-1 transmitted/founder viruses but only marginally affects the neutralizing activity of tested antibodies, suggesting their potential for microbicide application. Our findings underscore the need to consider semen-mediated enhancement when evaluating and developing microbicides and highlight the potential of incorporating HIV-1 bNAbs in formulations to enhance efficacy and mitigate HIV-1 transmission during sexual encounters.IMPORTANCEThis study examined the impact of semen on the development of microbicides, substances used to prevent the transmission of HIV-1 during sexual activity. Semen contains certain components that can render the virus more infectious, posing a challenge to microbicide effectiveness. Researchers specifically investigated the effect of semen on a group of powerful antibodies called broadly neutralizing antibodies, which can neutralize a large spectrum of different HIV-1 variants. The results revealed that semen only had a minimal effect on the antibodies' ability to neutralize the virus. This is promising because it suggests that these antibodies could still be effective in microbicides, even in the presence of semen. Understanding this interaction is crucial for developing better strategies to prevent HIV-1 transmission. By incorporating the knowledge gained from this study, scientists can now focus on creating microbicides that consider the impact of semen, bringing us closer to more effective prevention methods.
MeSH term(s)	Humans ; Anti-Infective Agents/pharmacology ; Antibodies, Neutralizing ; Antiviral Agents/pharmacology ; Broadly Neutralizing Antibodies/pharmacology ; HIV Antibodies ; HIV Infections/transmission ; HIV-1/physiology ; Semen/chemistry ; Semen/virology
Chemical Substances	Anti-Infective Agents ; Antibodies, Neutralizing ; Antiviral Agents ; Broadly Neutralizing Antibodies ; HIV Antibodies
Language	English
Publishing date	2024-03-19
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.01190-23
Database	MEDical Literature Analysis and Retrieval System OnLINE

In stock of ZB MED Cologne/Königswinter

Zs.A 609: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (1.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

Details ▾
- See ZB MED holdings
- Order with fees

Article ; Online: The Transmembrane Protease TMPRSS2 as a Therapeutic Target for COVID-19 Treatment.

Wettstein, Lukas / Kirchhoff, Frank / Münch, Jan

International journal of molecular sciences

2022 Volume 23, Issue 3

Abstract: TMPRSS2 is a type II transmembrane protease with broad expression in epithelial cells of the respiratory and gastrointestinal tract, the prostate, and other organs. Although the physiological role of TMPRSS2 remains largely elusive, several endogenous ... ...

Abstract	TMPRSS2 is a type II transmembrane protease with broad expression in epithelial cells of the respiratory and gastrointestinal tract, the prostate, and other organs. Although the physiological role of TMPRSS2 remains largely elusive, several endogenous substrates have been identified. TMPRSS2 serves as a major cofactor in SARS-CoV-2 entry, and primes glycoproteins of other respiratory viruses as well. Consequently, inhibiting TMPRSS2 activity is a promising strategy to block viral infection. In this review, we provide an overview of the role of TMPRSS2 in the entry processes of different respiratory viruses. We then review the different classes of TMPRSS2 inhibitors and their clinical development, with a focus on COVID-19 treatment.
MeSH term(s)	COVID-19/drug therapy ; COVID-19/genetics ; Humans ; Molecular Targeted Therapy/methods ; Molecular Targeted Therapy/trends ; SARS-CoV-2/drug effects ; SARS-CoV-2/physiology ; Serine Endopeptidases/genetics ; Serine Endopeptidases/physiology ; Serine Proteinase Inhibitors/pharmacology ; Serine Proteinase Inhibitors/therapeutic use ; Virus Internalization/drug effects
Chemical Substances	Serine Proteinase Inhibitors ; Serine Endopeptidases (EC 3.4.21.-) ; TMPRSS2 protein, human (EC 3.4.21.-)
Language	English
Publishing date	2022-01-25
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms23031351
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

Article ; Online: The Transmembrane Protease TMPRSS2 as a Therapeutic Target for COVID-19 Treatment

Lukas Wettstein / Frank Kirchhoff / Jan Münch

International Journal of Molecular Sciences, Vol 23, Iss 1351, p

2022 Volume 1351

Abstract	TMPRSS2 is a type II transmembrane protease with broad expression in epithelial cells of the respiratory and gastrointestinal tract, the prostate, and other organs. Although the physiological role of TMPRSS2 remains largely elusive, several endogenous substrates have been identified. TMPRSS2 serves as a major cofactor in SARS-CoV-2 entry, and primes glycoproteins of other respiratory viruses as well. Consequently, inhibiting TMPRSS2 activity is a promising strategy to block viral infection. In this review, we provide an overview of the role of TMPRSS2 in the entry processes of different respiratory viruses. We then review the different classes of TMPRSS2 inhibitors and their clinical development, with a focus on COVID-19 treatment.
Keywords	TMPRSS2 ; coronavirus ; SARS-CoV-2 ; influenza ; protease inhibitor ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

Full text online

Full text

Inter-library loan at ZB MED

Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

Article ; Online: Structure-Based Design of High-Affinity and Selective Peptidomimetic Hepsin Inhibitors.

Knaff, Philip Maximilian / Müller, Patrick / Kersten, Christian / Wettstein, Lukas / Münch, Jan / Landfester, Katharina / Mailänder, Volker

Biomacromolecules

2022 Volume 23, Issue 6, Page(s) 2236–2242

Abstract: In many solid tumors, increased upregulation of transmembrane serine proteases (TTSPs) leads to an overactivation of growth factors, which promotes tumor progression. Here, we have used a combinatorial methodology to develop high-affinity tetrapeptidic ... ...

Abstract	In many solid tumors, increased upregulation of transmembrane serine proteases (TTSPs) leads to an overactivation of growth factors, which promotes tumor progression. Here, we have used a combinatorial methodology to develop high-affinity tetrapeptidic inhibitors. A previous virtual screening of 8000 peptide combinations against the crystal structure of the TTSP hepsin identified a series of recognition sequences, customized for the non-prime substrate binding (P) sites of this serine protease. A combination of the top recognition sequences with an electrophilic warhead resulted in highly potent inhibitors with good selectivity against coagulation proteases factor Xa and thrombin. Structure-activity relationships of two selected compounds were further elucidated by investigation of their stability in biological fluids as well as the influence of the warhead and truncated inhibitors on the inhibitory potency. Overall, this methodology yielded compounds as selective inhibitors for potential cancer drug development, where hepsin is overexpressed.
MeSH term(s)	Drug Design ; Peptidomimetics/pharmacology ; Serine Endopeptidases/chemistry ; Serine Proteases ; Serine Proteinase Inhibitors/chemistry ; Serine Proteinase Inhibitors/metabolism ; Serine Proteinase Inhibitors/pharmacology ; Structure-Activity Relationship
Chemical Substances	Peptidomimetics ; Serine Proteinase Inhibitors ; Serine Proteases (EC 3.4.-) ; Serine Endopeptidases (EC 3.4.21.-) ; hepsin (EC 3.4.21.-)
Language	English
Publishing date	2022-05-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1526-4602
ISSN (online)	1526-4602
DOI	10.1021/acs.biomac.1c01011
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

Inter-library loan at ZB MED

Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

Article: Structure-Based Design of High-Affinity and Selective Peptidomimetic Hepsin Inhibitors

Knaff, Philip Maximilian / Müller, Patrick / Kersten, Christian / Wettstein, Lukas / Münch, Jan / Landfester, Katharina / Mailänder, Volker

Biomacromolecules. 2022 May 20, v. 23, no. 6

2022

Abstract	In many solid tumors, increased upregulation of transmembrane serine proteases (TTSPs) leads to an overactivation of growth factors, which promotes tumor progression. Here, we have used a combinatorial methodology to develop high-affinity tetrapeptidic inhibitors. A previous virtual screening of 8000 peptide combinations against the crystal structure of the TTSP hepsin identified a series of recognition sequences, customized for the non-prime substrate binding (P) sites of this serine protease. A combination of the top recognition sequences with an electrophilic warhead resulted in highly potent inhibitors with good selectivity against coagulation proteases factor Xa and thrombin. Structure–activity relationships of two selected compounds were further elucidated by investigation of their stability in biological fluids as well as the influence of the warhead and truncated inhibitors on the inhibitory potency. Overall, this methodology yielded compounds as selective inhibitors for potential cancer drug development, where hepsin is overexpressed.
Keywords	Lewis acids ; antineoplastic agents ; coagulation ; crystal structure ; drug development ; neoplasm progression ; peptides ; thrombin
Language	English
Dates of publication	2022-0520
Size	p. 2236-2242.
Publishing place	American Chemical Society
Document type	Article
ISSN	1526-4602
DOI	10.1021/acs.biomac.1c01011
Database	NAL-Catalogue (AGRICOLA)

Order via subito

Inter-library loan at ZB MED

Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

Article ; Online: Dual concentration-dependent effect of ascorbic acid on PAP(248-286) amyloid formation and SEVI-mediated HIV infection.

Mohapatra, Satabdee / Viswanathan, Guru Krishna Kumar / Wettstein, Lukas / Arad, Elad / Paul, Ashim / Kumar, Vijay / Jelinek, Raz / Münch, Jan / Segal, Daniel

RSC chemical biology

2021 Volume 2, Issue 5, Page(s) 1534–1545

Abstract: Human semen contains various amyloidogenic peptides derived from Prostatic Acid Phosphatase (PAP) and Semenogelin proteins that are capable of enhancing HIV-1 infection when assembled into fibrils. The best characterized among them is a 39 amino acid ... ...

Abstract	Human semen contains various amyloidogenic peptides derived from Prostatic Acid Phosphatase (PAP) and Semenogelin proteins that are capable of enhancing HIV-1 infection when assembled into fibrils. The best characterized among them is a 39 amino acid peptide PAP(248-286), which forms amyloid fibrils termed SEVI (semen-derived enhancer of viral infection) that increase the infectivity of HIV-1 by orders of magnitude. Inhibiting amyloid formation by PAP(248-286) may mitigate the sexual transmission of HIV-1. Several vitamins have been shown to reduce the aggregation of amyloids such as Aβ, α-Synuclein, and Tau, which are associated with neurodegenerative diseases. Since ascorbic acid (AA, vitamin C) is the most abundant vitamin in semen with average concentrations of 0.4 mM, we here examined how AA affects PAP(248-286) aggregation
Language	English
Publishing date	2021-08-10
Publishing country	England
Document type	Journal Article
ISSN	2633-0679
ISSN (online)	2633-0679
DOI	10.1039/d1cb00084e
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

Inter-library loan at ZB MED

Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

Article ; Online: Peptidomimetic inhibitors of TMPRSS2 block SARS-CoV-2 infection in cell culture.

Wettstein, Lukas / Knaff, Philip Maximilian / Kersten, Christian / Müller, Patrick / Weil, Tatjana / Conzelmann, Carina / Müller, Janis A / Brückner, Maximilian / Hoffmann, Markus / Pöhlmann, Stefan / Schirmeister, Tanja / Landfester, Katharina / Münch, Jan / Mailänder, Volker

Communications biology

2022 Volume 5, Issue 1, Page(s) 681

Abstract: The transmembrane serine protease 2 (TMPRSS2) primes the SARS-CoV-2 Spike (S) protein for host cell entry and represents a promising target for COVID-19 therapy. Here we describe the in silico development and in vitro characterization of peptidomimetic ... ...

Abstract	The transmembrane serine protease 2 (TMPRSS2) primes the SARS-CoV-2 Spike (S) protein for host cell entry and represents a promising target for COVID-19 therapy. Here we describe the in silico development and in vitro characterization of peptidomimetic TMPRSS2 inhibitors. Molecular docking studies identified peptidomimetic binders of the TMPRSS2 catalytic site, which were synthesized and coupled to an electrophilic serine trap. The compounds inhibit TMPRSS2 while demonstrating good off-target selectivity against selected coagulation proteases. Lead candidates are stable in blood serum and plasma for at least ten days. Finally, we show that selected peptidomimetics inhibit SARS-CoV-2 Spike-driven pseudovirus entry and authentic SARS-CoV-2 infection with comparable efficacy as camostat mesylate. The peptidomimetic TMPRSS2 inhibitors also prevent entry of recent SARS-CoV-2 variants of concern Delta and Omicron BA.1. In sum, our study reports antivirally active and stable TMPRSS2 inhibitors with prospects for further preclinical and clinical development as antiviral agents against SARS-CoV-2 and other TMPRSS2-dependent viruses.
MeSH term(s)	COVID-19/drug therapy ; Cell Culture Techniques ; Humans ; Molecular Docking Simulation ; Peptidomimetics/pharmacology ; SARS-CoV-2 ; Serine Endopeptidases/genetics
Chemical Substances	Peptidomimetics ; Serine Endopeptidases (EC 3.4.21.-) ; TMPRSS2 protein, human (EC 3.4.21.-)
Language	English
Publishing date	2022-07-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-022-03613-4
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

Inter-library loan at ZB MED

Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

Article ; Online: Isolation and Characterization of Neutralizing Monoclonal Antibodies from a Large Panel of Murine Antibodies against RBD of the SARS-CoV-2 Spike Protein.

D'Acunto, Emanuela / Muzi, Alessia / Marchese, Silvia / Donnici, Lorena / Chiarini, Valerio / Bucci, Federica / Pavoni, Emiliano / Ferrara, Fabiana Fosca / Cappelletti, Manuela / Arriga, Roberto / Serrao, Silvia Maria / Peluzzi, Valentina / Principato, Eugenia / Compagnone, Mirco / Pinto, Eleonora / Luberto, Laura / Stoppoloni, Daniela / Lahm, Armin / Groß, Rüdiger /

Seidel, Alina / Wettstein, Lukas / Münch, Jan / Goodhead, Andrew / Parisot, Judicael / De Francesco, Raffaele / Ciliberto, Gennaro / Marra, Emanuele / Aurisicchio, Luigi / Roscilli, Giuseppe

Antibodies (Basel, Switzerland)

2024 Volume 13, Issue 1

Abstract: The COVID-19 pandemic, once a global crisis, is now largely under control, a testament to the extraordinary global efforts involving vaccination and public health measures. However, the relentless evolution of SARS-CoV-2, leading to the emergence of new ... ...

Abstract	The COVID-19 pandemic, once a global crisis, is now largely under control, a testament to the extraordinary global efforts involving vaccination and public health measures. However, the relentless evolution of SARS-CoV-2, leading to the emergence of new variants, continues to underscore the importance of remaining vigilant and adaptable. Monoclonal antibodies (mAbs) have stood out as a powerful and immediate therapeutic response to COVID-19. Despite the success of mAbs, the evolution of SARS-CoV-2 continues to pose challenges and the available antibodies are no longer effective. New variants require the ongoing development of effective antibodies. In the present study, we describe the generation and characterization of neutralizing mAbs against the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein by combining plasmid DNA and recombinant protein vaccination. By integrating genetic immunization for rapid antibody production and the potent immune stimulation enabled by protein vaccination, we produced a rich pool of antibodies, each with unique binding and neutralizing specificities, tested with the ELISA, BLI and FACS assays and the pseudovirus assay, respectively. Here, we present a panel of mAbs effective against the SARS-CoV-2 variants up to Omicron BA.1 and BA.5, with the flexibility to target emerging variants. This approach ensures the preparedness principle is in place to address SARS-CoV-2 actual and future infections.
Language	English
Publishing date	2024-01-05
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2661514-9
ISSN	2073-4468 ; 2073-4468
ISSN (online)	2073-4468
ISSN	2073-4468
DOI	10.3390/antib13010005
Database	MEDical Literature Analysis and Retrieval System OnLINE

Order via subito

Article ; Online: Native and activated antithrombin inhibits TMPRSS2 activity and SARS-CoV-2 infection.

Wettstein, Lukas / Immenschuh, Patrick / Weil, Tatjana / Conzelmann, Carina / Almeida-Hernández, Yasser / Hoffmann, Markus / Kempf, Amy / Nehlmeier, Inga / Lotke, Rishikesh / Petersen, Moritz / Stenger, Steffen / Kirchhoff, Frank / Sauter, Daniel / Pöhlmann, Stefan / Sanchez-Garcia, Elsa / Münch, Jan

Journal of medical virology

2022 Volume 95, Issue 1, Page(s) e28124

Abstract: Host cell proteases such as TMPRSS2 are critical determinants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) tropism and pathogenesis. Here, we show that antithrombin (AT), an endogenous serine protease inhibitor regulating coagulation, ... ...

Abstract	Host cell proteases such as TMPRSS2 are critical determinants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) tropism and pathogenesis. Here, we show that antithrombin (AT), an endogenous serine protease inhibitor regulating coagulation, is a broad-spectrum inhibitor of coronavirus infection. Molecular docking and enzyme activity assays demonstrate that AT binds and inhibits TMPRSS2, a serine protease that primes the Spike proteins of coronaviruses for subsequent fusion. Consequently, AT blocks entry driven by the Spikes of SARS-CoV, MERS-CoV, hCoV-229E, SARS-CoV-2 and its variants of concern including Omicron, and suppresses lung cell infection with genuine SARS-CoV-2. Thus, AT is an endogenous inhibitor of SARS-CoV-2 that may be involved in COVID-19 pathogenesis. We further demonstrate that activation of AT by anticoagulants, such as heparin or fondaparinux, increases the anti-TMPRSS2 and anti-SARS-CoV-2 activity of AT, suggesting that repurposing of native and activated AT for COVID-19 treatment should be explored.
MeSH term(s)	Humans ; COVID-19 ; Antithrombins/pharmacology ; Cell Line ; COVID-19 Drug Treatment ; Molecular Docking Simulation ; SARS-CoV-2/metabolism ; Virus Internalization ; Anticoagulants/pharmacology ; Anticoagulants/therapeutic use ; Spike Glycoprotein, Coronavirus/metabolism ; Serine Endopeptidases/genetics
Chemical Substances	Antithrombins ; Anticoagulants ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; TMPRSS2 protein, human (EC 3.4.21.-) ; Serine Endopeptidases (EC 3.4.21.-)
Language	English
Publishing date	2022-09-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	752392-0
ISSN	1096-9071 ; 0146-6615
ISSN (online)	1096-9071
ISSN	0146-6615
DOI	10.1002/jmv.28124
Database	MEDical Literature Analysis and Retrieval System OnLINE

Full text online

Accessible to users with ZB MED library card

In stock of ZB MED Cologne/Königswinter

Zs.A 1320: Show issues

Location:
Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (1.OG)
ab Jg. 2022: Lesesaal (EG)

Order via subito

Details ▾

To top

Full text online

More links

Kategorien

Inter-library loan at ZB MED

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

Order via subito

Full text online

More links

Kategorien

Inter-library loan at ZB MED

More links

Kategorien

Order via subito

Inter-library loan at ZB MED

More links

Kategorien

Order via subito

Inter-library loan at ZB MED

More links

Kategorien

Order via subito

Inter-library loan at ZB MED

More links

Kategorien

Order via subito

Inter-library loan at ZB MED

More links

Kategorien

Order via subito

Full text online

More links

Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito