| 1. |
- Hoffmann, Markus, et al.
(author)
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Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity
- 2021
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In: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 65
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Journal article (peer-reviewed)abstract
- Background: Antivirals are needed to combat the COVID-19 pandemic, which is caused by SARS-CoV-2. The clinically-proven protease inhibitor Camostat mesylate inhibits SARS-CoV-2 infection by blocking the virus-activating host cell protease TMPRSS2. However, antiviral activity of Camostat mesylate metabolites and potential viral resistance have not been analyzed. Moreover, antiviral activity of Camostat mesylate in human lung tissue remains to be demonstrated. Methods: We used recombinant TMPRSS2, reporter particles bearing the spike protein of SARS-CoV-2 or authentic SARS-CoV-2 to assess inhibition of TMPRSS2 and viral entry, respectively, by Camostat mesylate and its metabolite GBPA. Findings: We show that several TMPRSS2-related proteases activate SARS-CoV-2 and that two, TMPRSS11D and TMPRSS13, are robustly expressed in the upper respiratory tract. However, entry mediated by these proteases was blocked by Camostat mesylate. The Camostat metabolite GBPA inhibited recombinant TMPRSS2 with reduced efficiency as compared to Camostat mesylate. In contrast, both inhibitors exhibited similar antiviral activity and this correlated with the rapid conversion of Camostat mesylate into GBPA in the presence of serum. Finally, Camostat mesylate and GBPA blocked SARS-CoV-2 spread in human lung tissue ex vivo and the related protease inhibitor Nafamostat mesylate exerted augmented antiviral activity. Interpretation: Our results suggest that SARS-CoV-2 can use TMPRSS2 and closely related proteases for spread in the upper respiratory tract and that spread in the human lung can be blocked by Camostat mesylate and its metabolite GBPA. Funding: NIH, Damon Runyon Foundation, ACS, NYCT, DFG, EU, Berlin Mathematics center MATH+, BMBF, Lower Saxony, Lundbeck Foundation, Novo Nordisk Foundation.
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| 2. |
- Löw, Karin, et al.
(author)
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Luminescent reporter cells enable the identification of broad-spectrum antivirals against emerging viruses
- 2023
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In: Journal of Medical Virology. - : John Wiley & Sons. - 0146-6615 .- 1096-9071. ; 95:11
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Journal article (peer-reviewed)abstract
- The emerging viruses SARS-CoV-2 and arenaviruses cause severe respiratory and hemorrhagic diseases, respectively. The production of infectious particles of both viruses and virus spread in tissues requires cleavage of surface glycoproteins (GPs) by host proprotein convertases (PCs). SARS-CoV-2 and arenaviruses rely on GP cleavage by PCs furin and subtilisin kexin isozyme-1/site-1 protease (SKI-1/S1P), respectively. We report improved luciferase-based reporter cell lines, named luminescent inducible proprotein convertase reporter cells that we employ to monitor PC activity in its authentic subcellular compartment. Using these sensor lines we screened a small compound library in high-throughput manner. We identified 23 FDA-approved small molecules, among them monensin which displayed broad activity against furin and SKI-1/S1P. Monensin inhibited arenaviruses and SARS-CoV-2 in a dose-dependent manner. We observed a strong reduction in infectious particle release upon monensin treatment with little effect on released genome copies. This was reflected by inhibition of SARS-CoV-2 spike processing suggesting the release of immature particles. In a proof of concept experiment using human precision cut lung slices, monensin potently inhibited SARS-CoV-2 infection, evidenced by reduced infectious particle release. We propose that our PC sensor pipeline is a suitable tool to identify broad-spectrum antivirals with therapeutic potential to combat current and future emerging viruses.
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| 3. |
- Popovski, Petar, et al.
(author)
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EU FP7 INFSO-ICT-317669 METIS, D2.1, Requirement analysis and design approaches for 5G air interface
- 2013
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Reports (other academic/artistic)abstract
- This document describes the problem space for the METIS research conducted in the radio link context. Firstly, a requirement analysis for the air interface design is conducted based on the test case descriptions presented in METIS deliverable D1.1. It follows an introduction of the research topics being pursued in the radio link research together with an illustration of how these topics are addressing the derived requirements. Moreover, it is shown which of thoserequirements address the needs of the METIS horizontal topics. To facilitate the achievement of these three objectives, a framework of General Requirements is introduced, which will be used throughout the project to assess and evaluate developed radio link solutions and to allow for measuring against the overall system performance goals.
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| 4. |
- Popovski, Petar, et al.
(author)
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EU FP7 INFSO-ICT-317669 METIS, D2.2 Novel radio link concepts and state of the art analysis
- 2013
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Reports (other academic/artistic)abstract
- This document provides a detailed overview of the Radio Link concepts being developed in METIS as well as a detailed analysis of the related state of the art. For each of the research topics identified for the radio link research covering flexible air interface, new waveforms,modulation and coding techniques as well as multiple access, medium access control and enablers for radio resource management, a detailed description of the aspects to be investigated will be given, going beyond the limits imposed by the systems operated today and their planned evolutions. The state of the art analysis, which is conducted for each of the research topics separately, covers current standards, their future evolutions as well as latest academic research. Elaborating on how the approaches followed in the radio link research may advance this state of the art carves a promising track towards innovative solutions addressing the challenges of future wireless communication.
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| 5. |
- Popovski, Petar, et al.
(author)
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EU FP7 INFSO-ICT-317669 METIS, D2.3 Components of a new air interface - building blocks and performance
- 2014
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Reports (other academic/artistic)abstract
- This document provides intermediate results of the concepts being developed in the radio link research of METIS. For each of the technology components (TeC) within the technology component clusters (TeCC), covering flexible air interface, new waveforms, modulation and coding techniques as well as multiple access, medium access control and enablers for radio resource management, key findings and conclusions collected so far are summarized in section 2. Continuative descriptions and research outcomes are given in the annex and referred publications.The results presented here will be extended in the further progress of the project, and they will be used in the next phase of the project to develop and refine the overall METIS system concept instantiated by the horizontal topics. The suitability of the single technology components for the overall system design being able to meet the wide range of requirements for 5G will then be evaluated.
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| 6. |
- Popovski, Petar, et al.
(author)
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EU FP7 INFSO-ICT-317669 METIS, D2.4 Proposed solutions for new radio access
- 2015
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Reports (other academic/artistic)abstract
- This deliverable represents the final report on the METIS radio link research. It provides a comprehensive and self-contained summary of all investigated technology components (TeCs), including evaluation results and conclusions on their potential for 5G. The METIS radio link research covers three main areas, which are considered key aspects for developing a self-contained air interface design for 5G: 1) Flexible air interface, 2) Waveforms, coding & modulation and transceiver design and 3) Multiple access, Medium Access Control (MAC) and Radio Resource Management (RRM). TeCs with similar research context and objectives have been grouped into clusters, whereof five have been selected as the most promising for 5G systems: From research area 1, TeC clusters providing key enablers for an air interface for ultra-dense networks (UDN) and for moving networks; from research area 2, multi-carrier transmission schemes with filtering; and from research area 3, novel access schemes for massive machine access as well as for non-orthogonal access.
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| 7. |
- Zamora, Juan Carlos, et al.
(author)
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Considerations and consequences of allowing DNA sequence data as types of fungal taxa
- 2018
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In: IMA Fungus. - : INT MYCOLOGICAL ASSOC. - 2210-6340 .- 2210-6359. ; 9:1, s. 167-185
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Journal article (peer-reviewed)abstract
- Nomenclatural type definitions are one of the most important concepts in biological nomenclature. Being physical objects that can be re-studied by other researchers, types permanently link taxonomy (an artificial agreement to classify biological diversity) with nomenclature (an artificial agreement to name biological diversity). Two proposals to amend the International Code of Nomenclature for algae, fungi, and plants (ICN), allowing DNA sequences alone (of any region and extent) to serve as types of taxon names for voucherless fungi (mainly putative taxa from environmental DNA sequences), have been submitted to be voted on at the 11th International Mycological Congress (Puerto Rico, July 2018). We consider various genetic processes affecting the distribution of alleles among taxa and find that alleles may not consistently and uniquely represent the species within which they are contained. Should the proposals be accepted, the meaning of nomenclatural types would change in a fundamental way from physical objects as sources of data to the data themselves. Such changes are conducive to irreproducible science, the potential typification on artefactual data, and massive creation of names with low information content, ultimately causing nomenclatural instability and unnecessary work for future researchers that would stall future explorations of fungal diversity. We conclude that the acceptance of DNA sequences alone as types of names of taxa, under the terms used in the current proposals, is unnecessary and would not solve the problem of naming putative taxa known only from DNA sequences in a scientifically defensible way. As an alternative, we highlight the use of formulas for naming putative taxa (candidate taxa) that do not require any modification of the ICN.
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