DE102016002873A1 - Cell detection and screening of substance libraries for the identification of individual substances that are effective in the case of a bioterrorist threat to mixtures of synthetic viruses - Google Patents

Cell detection and screening of substance libraries for the identification of individual substances that are effective in the case of a bioterrorist threat to mixtures of synthetic viruses Download PDF

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DE102016002873A1
DE102016002873A1 DE102016002873.4A DE102016002873A DE102016002873A1 DE 102016002873 A1 DE102016002873 A1 DE 102016002873A1 DE 102016002873 A DE102016002873 A DE 102016002873A DE 102016002873 A1 DE102016002873 A1 DE 102016002873A1
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Anmelder Gleich
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/02—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving viable microorganisms
    • C12Q1/18—Testing for antimicrobial activity of a material
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/502—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects
    • G01N33/5023—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects on expression patterns

Abstract

Zell-basiertes Screeningverfahren, mit dem Wirkstoffe gegen Mischungen verschiedener Typen synthetischer Viren identifiziert werden können.Cell-based screening method that identifies drugs against mixtures of different types of synthetic viruses.

Description

Die Suche nach Wirkstoffen zur Hemmung der Virusvermehrung konzentriert sich bisher auf in der Natur vorkommende einzelne Virustypen [z. B. HIV nach Anspruch 5 der DE 10 2014 005 975 B3 oder Ebolavirus nach Anspruch 3 der DE 10 2014 015 077 B3 ]. Hier wird nun ein Screeningverfahren vorgeschlagen, mit dem Wirkstoffe gegen Mischungen verschiedener Typen synthetischer Viren, die also mit den Mitteln der Synthetischen Biologie erzeugt wurden, identifiziert werden. Viren mit komplett synthetischem Genom wurden bereits von Craig Venter und Kollegen hergestellt [ Smith et al. 2003, PNAS 100 (26), Seiten 15440–15445: Generating a synthetic genome by whole genome assembly: φX174 bacteriophage from synthetic oligonucleotides ].The search for agents to inhibit virus replication has so far focused on naturally occurring single virus types [e.g. B. HIV according to claim 5 of DE 10 2014 005 975 B3 or Ebola virus according to claim 3 of DE 10 2014 015 077 B3 ]. Here, a screening method is proposed, with the active ingredients against mixtures of different types of synthetic viruses, which were thus generated by the means of synthetic biology identified. Fully synthetic genome viruses have already been prepared by Craig Venter and colleagues [ Smith et al. 2003, PNAS 100 (26), pages 15440-15445: Generating a synthetic genome by whole genome assembly: φX174 bacteriophage from synthetic oligonucleotides ].

Die Virustypen-Mischungen der vorliegenden Anmeldung enthalten:

  • a) Einzelsträngige (+)-Polarität RNA-Viren: Flaviviren (Zikavirus ZIKV),
  • b) Retroviren: Lentiviren (AIDS-Virus HIV), und
  • c) Einzelsträngige (–)-Polarität RNA-Viren: Orthomyxoviren (Influenzavirus) und Filoviren (Ebolavirus),
insbesondere eine Mischung enthaltend Virionen mit synthetischen Genomen von Zikavirus, HIV, Influenzavirus und Ebolavirus. Technischer Gedanke hinter diesem Vorschlag ist, dass die synergetische Wirkung dieser vier Virustypen die Molekularbiologie der Zelle auf andere Weise moduliert als jeder einzelne Virustyp für sich genommen, und dass damit auch bisher wirksame antivirale Stoffe ihre Wirksamkeit verlieren. Es sollen also neue Wirkstoffe gefunden werden, die bei einem Angriff aller vier Virustypen zugleich auf die Zelle abwehrend wirksam sind.The virus-type mixtures of the present application contain:
  • a) single-stranded (+) polarity RNA viruses: flaviviruses (zikavirus ZIKV),
  • b) retroviruses: lentiviruses (AIDS virus HIV), and
  • c) single-stranded (-) polarity RNA viruses: orthomyxoviruses (influenza virus) and filoviruses (Ebola virus),
in particular a mixture containing virions with synthetic genomes of Zikavirus, HIV, influenza virus and Ebola virus. The technical idea behind this proposal is that the synergetic effect of these four types of virus modulates the molecular biology of the cell in a different way than any single type of virus taken alone, and that so far effective antiviral substances lose their effectiveness. So it should be found new agents that are effective in an attack of all four types of virus at the same time defending the cell.

In einem ersten Schritt wird die anmeldungsgemäße Mischung dieser vier Virustypen mehrzelligen Modellorganismen auf natürliche Weise verabreicht oder direkt vom Genom synthetischer Testzellen aus exprimiert; entsprechend Absatz [0002] der DE 10 2014 015 077 B3 werden diese Testzellen im Folgenden wiederum bezeichnet als Vi-Zellen, die aber anstatt wie im Stand der Technik nur einen Virustyp nun anmeldungsgemäß hier die vier oben genannten Virustypen vermehren.In a first step, the mixture according to the application of these four virus types is administered in a natural manner to multicellular model organisms or expressed directly from the genome of synthetic test cells; according to paragraph [0002] of DE 10 2014 015 077 B3 These test cells are again referred to below as Vi cells, but instead of multiplying as in the prior art only one virus type according to the application here the four types of virus mentioned above.

In einem zweiten Schritt wird eine Stoffbibliothek von organisch-chemischen Stoffen (Small Organic Molecules), enthaltend mindestens 1.000 verschiedene, pharmakologisch sinnvolle Gemische von vier Komponenten in Form von Einzel-Erzeugnisgemischen als Bibliotheksmitgliedern bereitgestellt und mit diesen Modellorganismen oder den Vi-Zellen in Kontakt gebracht.In a second step, a substance library of organic chemicals (Small Organic Molecules) containing at least 1,000 different pharmacologically meaningful mixtures of four components in the form of single product mixtures are provided as library members and brought into contact with these model organisms or the Vi cells ,

In einem dritten Schritt wird eine veränderte Genexpression von Schlüsselgenen in den Zellen der Modellorganismen oder in den Vi-Zellen bestimmt, die das Vorliegen eines optimal wirksamen Einzel-Erzeugnisgemisches anzeigen. Dies entspricht dem Nachweis einer Input-Output-Transformation einer genetischen Information, siehe hierzu vollinhaltlich die technischen Ausführungen in der DE 10 2014 015 077 B3 , z. B. die Absätze [0005] bis [0013] und die Ansprüche 1 bis 6 dort.In a third step, altered gene expression of key genes is determined in the cells of the model organisms or in the Vi cells, indicating the presence of an optimally effective single product mixture. This corresponds to the proof of an input-output transformation of a genetic information, see in full the technical remarks in the DE 10 2014 015 077 B3 , z. For example, paragraphs [0005] to [0013] and claims 1 to 6 there.

Der Molekularvirologe ist ohne weiteres in der Lage, aus den in den Biosequenz-Datenbanken veröffentlichten Virusgenomen von Zikavirus, HIV, Influenzavirus und Ebolavirus geeignete Sequenzabschnitte herauszusuchen und diese in vitro zu synthetisieren, um sie z. B. in das Genom von Vi-Zellen zu integrieren, vgl. Anspruch 4 der DE 10 2014 015 077 B3 . Einzelne Sequenzabschnitts-Angaben sind daher in der vorliegenden Anmeldung unnötig.The molecular virologist is readily able to select suitable sequence segments from the virus genomes of zikavirus, HIV, influenza virus and ebolavirus published in the biosequence databases and to synthesize them in vitro in order to obtain them, for example. B. to integrate into the genome of Vi cells, cf. Claim 4 of DE 10 2014 015 077 B3 , Individual sequence segment information is therefore unnecessary in the present application.

An Einzelstoffen und deren Gemischen für die zu durchmusternden Stoffbibliotheken wird vorgeschlagen, die Zellreaktion der Modellorganismen oder der Vi-Zellen versuchsweise zu beobachten und zu standardisieren, beispielsweise mit einer pharmazeutisch verträglichen Mischung aus

  • a) BCX4430 (gegen Ebolavirus eingesetzt, siehe DE 10 2014 015 077 B3 Absatz [0003] zum Stand der Technik WO 2012/051570 A1 ),
  • b) Oseltamivir (gegen Influenzavirus eingesetzt),
  • c) Zidovudin (gegen HIV eingesetzt), und
  • d) Zistrosen-Extrakt (z. B. aus Cistus creticus nach EP 2 288 361 B1 ).
For individual substances and their mixtures for the substance libraries to be screened, it is proposed to experimentally observe and standardize the cell reaction of the model organisms or the Vi cells, for example with a pharmaceutically acceptable mixture of
  • a) BCX4430 (used against Ebola virus, see DE 10 2014 015 077 B3 Paragraph [0003] to the prior art WO 2012/051570 A1 )
  • b) oseltamivir (used against influenza virus),
  • c) zidovudine (used against HIV), and
  • d) Cistus extract (eg from Cistus creticus after EP 2 288 361 B1 ).

Zur Detektion der zellulären Reaktion wird wie in Anspruch 1 der DE 10 2014 015 077 B3 die Messung der Expressionsänderung der Gene TRAIL, IL-6, IL-18, IFN-beta, MIP-1 alpha und MIP-1 beta vorgeschlagen.For detecting the cellular reaction as in claim 1 of DE 10 2014 015 077 B3 proposed the measurement of the expression change of the genes TRAIL, IL-6, IL-18, IFN-beta, MIP-1 alpha and MIP-1 beta.

Entsprechend der DE 10 2014 015 077 B3 handelt es sich wiederum anmeldungsgemäß um einen Nachweis von natürlichen oder synthetischen, vermehrungsfähigen Vi-Zellen, genetisch vorprogrammiert oder de novo programmiert zur Funktion einer eine Organismen-Krisensituation-Aktivität imitierenden Input-Output-Transformation, bestehend darin, dass bei Kontakt mit einem Einzel-Erzeugnisgemisch einer Mischung aus den Erzeugnissen

  • 1) BCX4430,
  • 2) Oseltamivir,
  • 3) Zidovudin, und
  • 4) Zistrosen-Extrakt (z. B. aus Cistus creticus)
eine zelluläre Reaktion im Hinblick auf die Organismus-Krisensituation-Aktivität erfolgt, wobei die genetische Programmierung zur Funktion einer Organismen-Krisensituation-Aktivität die genetische Information der Gene TRAIL, IL-6, IL-18, IFN-beta, MIP-1 alpha und MIP-1 beta in den Vi-Zellen ist, die einen Input des zellulären Kontakts mit einem Einzel-Erzeugnisgemisch als Mitglied einer Erzeugnisgemisch-Bibliothek in einen Output der zellulären Reaktion in Form einer Veränderung der Expression der Gene TRAIL, IL-6, IL-18, IFN-beta, MIP-1 alpha und MIP-1 beta transformiert.According to the DE 10 2014 015 077 B3 In turn, according to the application, it is a detection of natural or synthetic, viable Vi cells, genetically preprogrammed or de novo programmed to function as an input-output transformation that mimics an organism crisis situation activity, consisting in that when in contact with an individual Product mixture of a mixture of the products
  • 1) BCX4430,
  • 2) Oseltamivir,
  • 3) Zidovudine, and
  • 4) Cistus extract (eg from Cistus creticus)
a cellular response occurs in terms of organism crisis situation activity, with genetic programming functioning as a function Organism crisis situation activity is the genetic information of the genes TRAIL, IL-6, IL-18, IFN-beta, MIP-1 alpha and MIP-1 beta in the Vi cells, which provide an input of cellular contact with a single cell. Product mixture as a member of a product mixture library transformed into an output of the cellular reaction in the form of a change in the expression of the genes TRAIL, IL-6, IL-18, IFN-beta, MIP-1 alpha and MIP-1 beta.

Die Vi-Zellen sind auf natürliche Weise infiziert mit den vier Virustypen, oder auf künstliche Weise versehen mit synthetischen Gesamtgenomen oder synthetischen Genomabschnitten oder synthetischen Genabschnitten der vier Virustypen. Als Organismus-Krisensituation wird anmeldungsgemäß eine auf Ebene der Modellorganismen oder der Vi-Zellen eintretende Erkrankung durch Befall mit den vier Virustypen definiert.The Vi cells are naturally infected with the four virus types, or artificially provided with synthetic total genomes or synthetic genome sections or synthetic gene sections of the four virus types. According to the application, a disease occurring at the level of the model organisms or the Vi cells is defined as an organism crisis situation by infestation with the four virus types.

Ein optimal auf Zellebene, auf Organebene oder auf Modellorganismenebene wirksames Erzeugnisgemisch ist entsprechend ein Mittel zur Linderung dieser Krisensituation. Der Pharmazeut ist in der Lage, die aufgefundenen optimal wirksamen Einzel-Erzeugnisgemische herzurichten, so dass die fertigen pharmazeutischen Formulierungen im Falle einer gleichzeitigen Ausbreitung der vier Virustypen, z. B. bei einem bioterroristischen Angriff, an die Bevölkerung ausgegeben werden können. Da anmeldungsgemäß nur Small Organic Molecules verwendet werden, sind die Formulierungen in großen Mengen lange Zeit lagerbar und benötigen keine Kühlkette wie Biologicals.A mixture of products optimally effective at the cellular, the organ or the model-organism level is accordingly a means of alleviating this crisis situation. The pharmacist is able to prepare the found optimally effective single product mixtures, so that the finished pharmaceutical formulations in the case of a simultaneous spread of the four virus types, eg. B. in a bioterrorist attack, can be spent on the population. Since, according to the application, only small organic molecules are used, the formulations can be stored in large quantities for a long time and do not require a cold chain such as biologicals.

Neben dem Bestand an genetischer Information aus den vier Virustypen können die Vi-Zellen an sich künstliche, mit in vitro synthetisierten menschlichen Minimal-Chromosomen ausgestattete Minimal-Zellen sein, die im natürlichen Menschen nicht vorkommen, und die einen für das vorliegende Nachweisverfahren optimierten, in der Natur in seiner Gesamtheit nicht vorkommenden menschlichen Gen-Satz umfassen, aufweisend mindestens die Gene TRAIL, IL-6, IL-18, IFN-beta, MIP-1 alpha und MIP-1 beta.In addition to the stock of genetic information from the four virus types, the Vi cells can be in itself artificial, minimal cells equipped with in vitro synthesized human minimal chromosomes, which do not occur in natural humans, and optimized for the present detection method, in comprising at least the gene TRAIL, IL-6, IL-18, IFN-beta, MIP-1 alpha and MIP-1 beta, which are not present in their entirety in their entirety.

Auf die technische Offenbarung der DE 10 2014 015 077 B3 wird vollinhaltlich Bezug genommen.On the technical disclosure of DE 10 2014 015 077 B3 is incorporated by reference.

ZITATE ENTHALTEN IN DER BESCHREIBUNG QUOTES INCLUDE IN THE DESCRIPTION

Diese Liste der vom Anmelder aufgeführten Dokumente wurde automatisiert erzeugt und ist ausschließlich zur besseren Information des Lesers aufgenommen. Die Liste ist nicht Bestandteil der deutschen Patent- bzw. Gebrauchsmusteranmeldung. Das DPMA übernimmt keinerlei Haftung für etwaige Fehler oder Auslassungen.This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Zitierte PatentliteraturCited patent literature

  • DE 102014005975 B3 [0001] DE 102014005975 B3 [0001]
  • DE 102014015077 B3 [0001, 0003, 0005, 0006, 0007, 0008, 0009, 0013] DE 102014015077 B3 [0001, 0003, 0005, 0006, 0007, 0008, 0009, 0013]
  • WO 2012/051570 A1 [0007] WO 2012/051570 A1 [0007]
  • EP 2288361 B1 [0007] EP 2288361 B1 [0007]

Zitierte Nicht-PatentliteraturCited non-patent literature

  • Smith et al. 2003, PNAS 100 (26), Seiten 15440–15445: Generating a synthetic genome by whole genome assembly: φX174 bacteriophage from synthetic oligonucleotides [0001] Smith et al. 2003, PNAS 100 (26), pages 15440-15445: Generating a synthetic genome by whole genome assembly: φX174 bacteriophage from synthetic oligonucleotides [0001]

Claims (1)

Nachweis von natürlichen oder synthetischen, vermehrungsfähigen Vi-Zellen, genetisch vorprogrammiert oder de novo programmiert zur Funktion einer eine Organismen-Krisensituation-Aktivität imitierenden Input-Output-Transformation, bestehend darin, dass bei Kontakt mit einem Einzel-Erzeugnisgemisch einer Mischung aus den Erzeugnissen 1) BCX4430, 2) Oseltamivir, 3) Zidovudin, und 4) Zistrosen-Extrakt eine zelluläre Reaktion im Hinblick auf die Organismus-Krisensituation-Aktivität erfolgt, wobei die genetische Programmierung zur Funktion einer Organismen-Krisensituation-Aktivität die genetische Information der Gene TRAIL, IL-6, IL-18, IFN-beta, MIP-1 alpha und MIP-1 beta in den Vi-Zellen ist, die einen Input des zellulären Kontakts mit einem Einzel-Erzeugnisgemisch als Mitglied einer Erzeugnisgemisch-Bibliothek in einen Output der zellulären Reaktion in Form einer Veränderung der Expression der Gene TRAIL, IL-6, IL-18, IFN-beta, MIP-1 alpha und MIP-1 beta transformiert, und wobei die Vi-Zellen auf künstliche Weise versehen sind mit synthetischen Gesamtgenomen oder synthetischen Genomabschnitten oder synthetischen Genabschnitten von: 1) Zikavirus, 2) HIV, 3) Influenzavirus, und 4) Ebolavirus.Detection of natural or synthetic, viable Vi cells, genetically preprogrammed or de novo programmed to function as an input of an organic crisis situation activity input-output transformation, consisting in that when in contact with a single product mixture of a mixture of the products 1) BCX4430, 2) Oseltamivir, 3) Zidovudine, and 4) Cistus extract there is a cellular response to the organism crisis situation activity, in which genetic programming for the function of an organism crisis situation activity the genetic information the genes TRAIL, IL-6, IL-18, IFN-beta, MIP-1 alpha and MIP-1 beta in the Vi cells, providing an input of the cellular contact with a single product mix as a member of a mix product library into an output of the cellular reaction in the form of a change in the expression of the genes TRAIL, IL-6, IL-18, IFN-beta, MIP-1 alpha and MIP-1 beta transformed, and where the Vi cells are artificially provided with synthetic total genomes or synthetic genome sections or synthetic gene sections of: 1) zika virus, 2) HIV, 3) influenza virus, and 4) Ebola virus.
DE102016002873.4A 2016-03-09 2016-03-09 Cell detection and screening of substance libraries for the identification of individual substances that are effective in the case of a bioterrorist threat to mixtures of synthetic viruses Withdrawn DE102016002873A1 (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012051570A1 (en) 2010-10-15 2012-04-19 Shanta Bantia Methods and compositions for inhibition of polymerase
EP2288361B1 (en) 2008-05-06 2013-08-21 Finzelberg GmbH & Co. KG Cistus extract containing enriched secondary plant ingredients
DE102014005975B3 (en) 2014-04-23 2015-02-05 Heinz Kiefer Detection of cell-implemented genetic information pre-programmed or de novo programmed, natural or synthetic replicable cells or minimal cells that respond to a product mixture for the purpose of a screening process
DE102014015077B3 (en) 2014-10-11 2015-04-02 Heinz Kiefer Detection of cell-implemented genetic information pre-programmed or de novo programmed, natural or synthetic viable Vi cells or minimal Vi cells that respond to a product mixture for the purpose of a screening process

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2288361B1 (en) 2008-05-06 2013-08-21 Finzelberg GmbH & Co. KG Cistus extract containing enriched secondary plant ingredients
WO2012051570A1 (en) 2010-10-15 2012-04-19 Shanta Bantia Methods and compositions for inhibition of polymerase
DE102014005975B3 (en) 2014-04-23 2015-02-05 Heinz Kiefer Detection of cell-implemented genetic information pre-programmed or de novo programmed, natural or synthetic replicable cells or minimal cells that respond to a product mixture for the purpose of a screening process
DE102014015077B3 (en) 2014-10-11 2015-04-02 Heinz Kiefer Detection of cell-implemented genetic information pre-programmed or de novo programmed, natural or synthetic viable Vi cells or minimal Vi cells that respond to a product mixture for the purpose of a screening process

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Smith et al. 2003, PNAS 100 (26), Seiten 15440-15445: Generating a synthetic genome by whole genome assembly: phiX174 bacteriophage from synthetic oligonucleotides

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