DE4432942A1 - New synthetic inducible biological response amplifier - Google Patents
New synthetic inducible biological response amplifierInfo
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- DE4432942A1 DE4432942A1 DE19944432942 DE4432942A DE4432942A1 DE 4432942 A1 DE4432942 A1 DE 4432942A1 DE 19944432942 DE19944432942 DE 19944432942 DE 4432942 A DE4432942 A DE 4432942A DE 4432942 A1 DE4432942 A1 DE 4432942A1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biophysics (AREA)
- Gastroenterology & Hepatology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
Eine Großzahl von derzeit sich entwickelnden Strategien zur Behandlung menschlicher Erkrankungen baut auf dem Wissen, das über die Genstruktur und die Genregulation erworben wurde. Dies hat zur Entwicklung von experimentellen Therapieformen geführt, wie z. B. Antisense-Oligodeoxynukleotiden (1), somatischer Gentherapie (2) sowie durch Gentransfer intrazellulär exprimierte Ribozyme (3) und Antikörper (4).A large number of currently developing treatment strategies human diseases builds on the knowledge that about the gene structure and the Gene regulation was acquired. This has led to the development of experimental Therapy forms, such as B. antisense oligodeoxynucleotides (1), somatic Gene therapy (2) and ribozymes (3) and expressed intracellularly by gene transfer Antibodies (4).
Eine parallel dazu sich entwickelnde Strategie mit vielversprechenden Aussichten ist die der therapeutischen Peptide. Beispiele dafür sind die experimentell erfolgreich getesteten Peptide gegen das AIDS-Virus (5) und gegen eine bestimmte Tumorart, das Lymphom (6). Darüber hinaus gibt es bereits klinisch eingesetzte Peptide mit eingeschränktem Wirkungsspektrum und mäßigen Erfolgen, so z. B. die GnRH-Analoga beim fortgeschrittenen Prostatakarzinom (7) und die Somatostatin-Analoga bei einer Reihe von endokrinologischen Tumoren (8).A strategy developing in parallel with a promising outlook is that of therapeutic peptides. Examples of this are experimentally successful peptides tested against the AIDS virus (5) and against a specific type of tumor, the Lymphoma (6). In addition, there are already clinically used peptides limited spectrum of activity and moderate success, such. B. the GnRH analogues in advanced prostate cancer (7) and the somatostatin analogues in one Series of endocrinological tumors (8).
Der Ansatz der Gentherapie bringt nach heutigem Kenntnisstand mehrere ungelöste Probleme mit sich, so z. B. die nur transiente Expression des in die Zellen transferierten Gens, die fehlende Kontrolle über die Stelle, an die das transferierte Gen ins Wirtsgenom eingebaut wird, das pathogene Potential einiger viraler Vektoren und die Möglichkeit des versehentlichen Einbaus dieser Gene in die Keimzellen, was unabsehbare Folgen für die betreffenden Nachkommen des damit behandelten Individuums hätte (2).According to current knowledge, the approach of gene therapy brings several unsolved problems with it, e.g. B. the only transient expression of the in the cells transferred gene, the lack of control over the location to which the transferred gene is built into the host genome, the pathogenic potential of some viral vectors and the Possibility of accidental incorporation of these genes into the germ cells what unforeseeable consequences for the descendants concerned of the treated with it Individual would have (2).
Bei den (unmodifizierten) Peptiden ergibt sich in vivo das Problem der geringen Halbwertszeit aufgrund proteolytischer Vorgänge. Andererseits ist die Steuerbarkeit von Peptiden, die so modifiziert wurden, daß sie resistenter gegen die in vivo-Proteolyse sind, gegenüber dem unveränderten Peptid verständlicherweise vermindert.The (unmodified) peptides have the problem of low in vivo Half-life due to proteolytic processes. On the other hand, the controllability of Peptides that have been modified to be more resistant to in vivo proteolysis are understandably reduced compared to the unchanged peptide.
Ein Weg heraus aus dem Dilemma der Peptid-Konstruktion (s. Problem) würde ein Peptid/Protein sein, das physiologischerweise nur in Anwesenheit des Krankheitserregers und seiner Bestandteile, allgemeiner des pathogenen Stimulus, wirksam ist. Im Grunde ist dies das Wesen der Immunantwort und der Produktion von Antikörpern, die biochemisch zu den Proteinen gehören. Leider lassen sich jedoch Antikörper nur gegen wenige Krankheiten einsetzen, und zwar in Form von passiven oder/und aktiven Antikörpern (letzteres entspricht dem Ergebnis der Schutzimpfung).A way out of the dilemma of peptide construction (see problem) would be be a peptide / protein that is physiologically only in the presence of the Pathogen and its components, more generally the pathogenic stimulus, is effective. Basically, this is the essence of the immune response and the production of Antibodies that are biochemically proteins. Unfortunately, however Use antibodies against only a few diseases, in the form of passive ones or / and active antibodies (the latter corresponds to the result of the vaccination).
Aus den genannten Gründen habe ich eine neue Form eines therapeutischen Peptids/Proteins konzipiert. Der Prototyp dieser artifiziellen Peptide heißt "Synthetic Inducible Biological Response Amplifier", kurz SIBRA (9). Als Vorbild für die Konzeption von SIBRA diente mir der natürlicherweise vorkommende, spezifische Transkriptionsfaktor AMT1 in Hefezellen, der für die Kupfer-Entgiftung verantwortlich ist (10). Demnach ist ein SIBRA so konzipiert, daß es pathogene Proteine neutralisiert und sich selbst vervielfacht, und zwar nur solange diese Proteine in der Zelle bzw. im Organismus anwesend sind, analog zu dem dynamischen Verhältnis, das zwischen pathogenen Kupfer-Ionen und AMT1 bei der Hefe vorliegt.For the reasons mentioned, I have a new form of therapeutic Peptides / Proteins designed. The prototype of these artificial peptides is called "Synthetic Inducible Biological Response Amplifier ", SIBRA (9) for short. As a model for the The conception of SIBRA served me the naturally occurring, specific one Transcription factor AMT1 in yeast cells, which is responsible for the copper detoxification is (10). Accordingly, a SIBRA is designed to neutralize pathogenic proteins and multiplies itself, and only as long as these proteins in the cell or in Organism are present, analogous to the dynamic relationship that exists between pathogenic copper ions and AMT1 in yeast.
Das SIBRA soll aus einer Ligandbindungsdomäne, z. B. in Form eines Komplementärpeptids (11), einer DNA-Bindungsregion, z. B. vom Zinkfingertyp (12), einem trans-aktivierenden Segment (13) sowie weiteren kurzen Sequenzen bestehen, die das Einschleusen des SIBRA in das gewünschte Zellkompartiment bewerkstelligen. Diese kurzen Sequenzen wären z. B. eine Internalisierungssequenz (14) bzw. eine Fusionspeptidsequenz (15) für die Einschleusung des SIBRA aus dem Extrazellulärmilieu ins Zytosol der Zelle oder/und eine nukleäre Lokalisationssequenz (NLS) vom bipartiten Typ (9, 16) für die Einschleusung des SIBRA in den Zellkern (9). Diese Domänen würden vergleichbaren Domänen in zellulären Proteinen nachempfunden, artifiziell zu einem SIBRA geschneidert und weiter modifiziert werden zu einem Molekül, das in vivo und intrazellulär wirksam ist (9).The SIBRA is said to originate from a ligand binding domain, e.g. B. in the form of a Complementary peptide (11), a DNA binding region, e.g. B. of the zinc finger type (12), a trans-activating segment (13) and other short sequences that manage the introduction of the SIBRA into the desired cell compartment. These short sequences would be e.g. B. an internalization sequence (14) or Fusion peptide sequence (15) for the introduction of the SIBRA from the Extracellular environment in the cytosol of the cell and / or a nuclear localization sequence (NLS) of the bipartite type (9, 16) for the introduction of the SIBRA into the cell nucleus (9). These domains would be modeled on comparable domains in cellular proteins, artificially tailored into a SIBRA and further modified into a molecule, which is effective in vivo and intracellularly (9).
Da das SIBRA einem Wirtsprotein mit autoregulatorischen Eigenschaften ähneln soll, würde eben dieses SIBRA nach Exposition gegenüber einem definierten Umweltstimulus, sprich: einem pathogenen Protein, aktiviert werden und infolgedessen Wirtsantworten amplifizieren, die der angemessenen Abwehr des genannten Stimulus dienen (9). Daraufhin würden intrazelluläre Wirtsproteine akkumulieren, die mit dem Auslöser-SIBRA die weiter oben beschriebenen funktionellen Domänen gemeinsam haben und die Fähigkeit zur positiven Autoregulation besitzen (9). Letzterer Mechanismus mag die Interaktion des induzierten intrazellulären Wirtsproteins mit dem Promoter seines Gens beinhalten und somit eine direkte positiv-autoregulatorische Schleife bilden oder die Induktion von intermediären Proteinen erfordern, die schließlich die Produktion von SIBRA-ähnlichen Wirtsproteinen ankurbeln (9).Because the SIBRA resemble a host protein with autoregulatory properties should, this SIBRA would after exposure to a defined one Environmental stimulus, that is: a pathogenic protein, are activated and as a result Amplify host responses that adequately defend against the stimulus mentioned serve (9). Thereupon, intracellular host proteins would accumulate with the Trigger SIBRA shared the functional domains described above and have the ability for positive auto-regulation (9). The latter Mechanism likes the interaction of the induced intracellular host protein with that Promoters of his gene contain and thus a direct positive autoregulatory Loop or require the induction of intermediate proteins that eventually boost the production of SIBRA-like host proteins (9).
Wie soll die Aktivierung des SIBRA durch das pathogenene Protein funktionieren? Nach Andockung des pathogenen Proteins an die Ligandbindungsdomäne des SIBRA, würde eine Konformationsänderung des gesamten SIBRA erfolgen, in deren Folge die DNA-Bindungsregion und die trans-Aktivierungsdomäne des SIBRA aktiviert würden, d. h. sie wären nun in der Lage, mit hoher Affinität an den Promoter des Gens zu binden, das für das SIBRA-ähnliche, intrazelluläre Wirtsprotein kodiert. Damit würde die Produktion eben dieses Proteins in Gang gebracht werden, ein Prozeß, der durch die pathogenen Proteine aufrechterhalten und, nach deren vollständigen Eliminierung, wieder zum Stillstand kommen würde (9).How is the activation of SIBRA by the pathogenic protein function? After the pathogenic protein has docked to the ligand-binding domain of the SIBRA, a conformational change of the entire SIBRA would take place, in the Follow the DNA binding region and the trans activation domain of SIBRA activated would, d. H. they would now be able to affinity to the promoter of the gene with high affinity to bind, which encodes the SIBRA-like, intracellular host protein. That would the production of this protein can be started, a process which is carried out by the maintain pathogenic proteins and, after their complete elimination, again would come to a standstill (9).
Interessanterweise und im Einvernehmen mit den obigen Voraussetzungen für die Konstruktion von (antineoplastischen) SIBRAs ist bereits gezeigt worden, daß das Retinoblastomprotein (RB), ein zentraler Tumorsuppressor, eine positive Autoregulation und Autoamplifikation durchzuführen in der Lage ist (17). Folglich wäre es vielversprechend, ein SIBRA zu bauen, das sozusagen als "Mini-RB" fungiert, und dessen Einsatz im Organismus die Amplifikation schützender RB-Moleküle bzw. anderer RB-ähnlicher Moleküle wie z. B. p107 bewirken würde (9, 18). Dieses "Mini-RB" wäre das Ergebnis der Straffung der entscheidenden Sequenzen in RB, und zwar was Ligand- und DNA-Bindung sowie trans-Aktivierung und intrazelluläre bzw. intranukleäre Lokalisation angeht, bei gleichzeitiger Modifikation zwecks in vivo-Wirksamkeit (9, 18).Interestingly, and in agreement with the above requirements for Construction of (antineoplastic) SIBRAs has already been shown that the Retinoblastoma protein (RB), a central tumor suppressor, positive autoregulation and is capable of performing autoamplification (17). So it would be promising to build a SIBRA that functions as a "mini RB", and its use in the organism, the amplification of protective RB molecules or others RB-like molecules such as B. would cause p107 (9, 18). This would be "Mini-RB" the result of streamlining the crucial sequences in RB, which is what ligand- and DNA binding as well as trans activation and intracellular or intranuclear Localization is concerned, with simultaneous modification for in vivo effectiveness (9, 18).
Solchermaßen konstruierte und auf die jeweilige Krankheit(sproteine) zugeschneiderte SIBRAs, wie hier beschrieben, könnten sehr effiziente und nebenwirkungsarme Therapeutika sein, ob gegen individuelle Krebsformen oder gegen AIDS (9).So constructed and for the respective disease (sproteine) Tailored SIBRAs, as described here, could be very efficient and Therapeutics with few side effects, whether against individual forms of cancer or against AIDS (9).
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4. Marasco, W. A. et al (1993). Design, intracellular expression, and activity of a human anti-human immunodeficiency virus type 1 gp120 single-chain antibody. Proc. Natl. Acad. Sci. USA 90, 7889-7893.4. Marasco, W.A. et al (1993). Design, intracellular expression, and activity of a human anti-human immunodeficiency virus type 1 gp120 single-chain antibody. Proc. Natl. Acad. Sci. USA 90, 7889-7893.
5. Jiang, S. et al (1993). HIV-1 inhibition by a peptide. Nature 365, 113.5. Jiang, S. et al (1993). HIV-1 inhibition by a peptide. Nature 365, 113.
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7. Calabresi, P. and Chabner, B. A. (1991). "Antineoplastic agents" in Goodman & Gilman′s The pharmacological basis of therapeutics, ed. A. Goodman Gilman, T.W. Rall, A. S. Nies and P. Taylor, Maxwell Macmillan International Editions, Pergamon Press, New York. 7. Calabresi, P. and Chabner, B.A. (1991). "Antineoplastic agents" in Goodman & Gilman’s The pharmacological basis of therapeutics, ed. A. Goodman Gilman, T.W. Rall, A. S. Nies and P. Taylor, Maxwell Macmillan International Editions, Pergamon Press, New York.
Rall, A. S. Nies and P. Taylor, Maxwell Macmillan International Editions, Pergamon Press, New York.Rall, A. S. Nies and P. Taylor, Maxwell Macmillan International Editions, Pergamon Press, New York.
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10. Zhou, P. and Thiele, D. J. (1993). Rapid transcriptional autoregulation of a yeast metalloregulatory transcription factor is essential for high-level copper detoxification. Genes & Dev. 7, 1824-1835.10. Zhou, P. and Thiele, D.J. (1993). Rapid transcriptional autoregulation of a yeast metalloregulatory transcription factor is essential for high-level copper detoxification. Genes & Dev. 7, 1824-1835.
11. Blalock, J.E. (1990). Complementarity of peptides specified by "sense" and "antisense" strands of DNA. Trends Biotechnol. 8, 140-144.11. Blalock, J.E. (1990). Complementarity of peptides specified by "sense" and "antisense" strands of DNA. Trends in biotechnology. 8, 140-144.
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13. Gerber, M. P. et al. (1994). Transcriptional activation modulated by homopolymeric glutamine and proline stretches. Science 263, 808-810.13. Gerber, M.P. et al. (1994). Transcriptional activation modulated by homopolymeric glutamine and proline stretches. Science 263, 808-810.
14. Hopkins, C. R. (1992). Selective membrane protein trafficking: vectorial flow and filter. Trends Biochem. Sci. 17, 27-32.14. Hopkins, C.R. (1992). Selective membrane protein trafficking: vectorial flow and filter. Trends biochem. Sci. 17, 27-32.
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16. Radulescu, R. T. (1994). Nuclear localization signal in insulin-like growth factor binding protein type 3. Trends Biochem. Sci. 19, 278.16. Radulescu, R.T. (1994). Nuclear localization signal in insulin-like growth factor binding protein type 3. Trends Biochem. Sci. 19, 278.
17. Park, K. et al (1994). The human retinoblastoma susceptibility gene promoter is positively autoregulated by its own product. J. Biol. Chem. 269, 6083-6088.17. Park, K. et al (1994). The human retinoblastoma susceptibility gene promoter is positively autoregulated by its own product. J. Biol. Chem. 269, 6083-6088.
18. Radulescu, R. T. (1994) unpublished observation.18. Radulescu, R.T. (1994) unpublished observation.
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| DE19944432942 DE4432942A1 (en) | 1994-09-15 | 1994-09-15 | New synthetic inducible biological response amplifier |
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| DE19944432942 DE4432942A1 (en) | 1994-09-15 | 1994-09-15 | New synthetic inducible biological response amplifier |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998054209A2 (en) * | 1997-05-31 | 1998-12-03 | Peptide Therapeutics Limited | Human mast cell function-associated antigen (mafa) and uses thereof |
| EP0902088A2 (en) * | 1996-03-26 | 1999-03-17 | Razvan T. Radulescu | Peptides with antiproliferative properties |
-
1994
- 1994-09-15 DE DE19944432942 patent/DE4432942A1/en not_active Withdrawn
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0902088A2 (en) * | 1996-03-26 | 1999-03-17 | Razvan T. Radulescu | Peptides with antiproliferative properties |
| EP0902088A3 (en) * | 1996-03-26 | 1999-09-15 | Razvan T. Radulescu | Peptides with antiproliferative properties |
| WO1998054209A2 (en) * | 1997-05-31 | 1998-12-03 | Peptide Therapeutics Limited | Human mast cell function-associated antigen (mafa) and uses thereof |
| WO1998054209A3 (en) * | 1997-05-31 | 1999-03-11 | Peptide Therapeutics Ltd | Human mast cell function-associated antigen (mafa) and uses thereof |
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