DE4237129A1 - Application of complementary peptide(s) in oncology and cardiology - pref. using peptide(s) complementary to human papilloma virus type 16 onco-protein E7, binding to retino-blastoma proteins - Google Patents

Application of complementary peptide(s) in oncology and cardiology - pref. using peptide(s) complementary to human papilloma virus type 16 onco-protein E7, binding to retino-blastoma proteins

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DE4237129A1
DE4237129A1 DE19924237129 DE4237129A DE4237129A1 DE 4237129 A1 DE4237129 A1 DE 4237129A1 DE 19924237129 DE19924237129 DE 19924237129 DE 4237129 A DE4237129 A DE 4237129A DE 4237129 A1 DE4237129 A1 DE 4237129A1
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complementary
peptide
binding
insulin
protein
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Des Erfinders Auf Nennung Verzicht
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RADULESCU RAZVAN TUDOR DR MED
WENDTNER CLEMENS MARTIN
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RADULESCU RAZVAN TUDOR DR MED
WENDTNER CLEMENS MARTIN
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4736—Retinoblastoma protein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

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  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Toxicology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Claimed is the application of complementary peptides in oncology and cardiology. Potentially (i) a substance VPH (NH2 - Leu alpha N-Me-Phe Tyr Lys AlphaN-Me-Lys Val D-Tyr-COOH is anti-neoplastic; (ii) variation of the prim. structure of the peptide mimetic of calcium (Dillon, J. et al, Proc. Natl. Acad. Sci USA 88, 9726-9729) is an agent for hypertension or for tumours by inactivating the multi drug resistance gene prod.; (iii) peptide hSNI(B16-21) (3'-5', NH2 - Leu-Pro-Thr-His-Asp-Ala-COOH) is useful in diseases including tumours which occur together with insulin hyperproduction, and (iv) complementary proteins to insulin and insulin growth factors I and II are similar to the complementary peptides of oncoprotein E7 of the human papilloma virus type 16 and to the complementary peptides of the binding proteins binding to the retinoblastoma (RB) protein which regulates cell growth. Therefore, these proteins may be competitors for the RB-protein binding site, pref. binding RB protein 649-654. USE - The complementary peptides are administered to cancer patients as a potentially more potent anti-cancer agent which also shows fewer side effects than known agents. In the case of treatment of hypertension the suggested peptide mimetic of calcium could be an alternative to known calcium antagonists.

Description

Derzeitiger Stand der Technik/Forschung:Current state of technology / research:

a) Im Bereich der Onkologie gibt es zur Zeit mehrere bewährte, jedoch oft mit erheblichen Nebenwirkungen behaftete und nur zum Teil kurative Behandlungskonzepte. Dazu gehören Chemotherapie Strahlentherapie hormonelle Therapie und chirurgische Operationsverfahren. Zu den alternativen Behandlungskonzepten zählen die Gentherapie (9), die Behandlung mit toxingekoppelten monoklonalen Antikörpern (10), der adoptive Transfer von lymphokinaktivierten Lymphozyten (11), die Behandlung mit Fab-Fragmenten (12) und neuerdings, wie von uns vorgeschlagen, die Therapie mit spezifischen komplementären Peptiden, z. B. VPH (2) (siehe Fig. 1).a) In the field of oncology, there are currently several proven, but often with considerable side effects and only partially curative treatment concepts. These include chemotherapy, radiation therapy, hormonal therapy and surgical procedures. Alternative treatment concepts include gene therapy (9), treatment with toxin-coupled monoclonal antibodies (10), adoptive transfer of lymphokine-activated lymphocytes (11), treatment with Fab fragments (12) and more recently, as we have suggested, therapy with specific complementary peptides, e.g. B. VPH (2) (see Fig. 1).

b) Im Bereich der Kardiologie, speziell der Behandlung des Bluthochdrucks, werden Substanzen wie z. B. Betablocker, Diuretika, ACE-Hemmer und Kalziumantagonisten eingesetzt. Diese Gruppe von Antihypertensiva könnte bereichert und ihre Nebenwirkungen könnten minimalisiert werden durch Kalziumantagonisten, die auf der Grundlage der Komplementärpeptid- Theorie entwickelt werden (4).b) in the field of cardiology, especially the treatment of high blood pressure, are substances such as B. beta blockers, diuretics, ACE inhibitors and Calcium antagonists used. This group of antihypertensive drugs could enriched and their side effects could be minimized by Calcium channel blockers, which are based on the complementary peptide Theory to be developed (4).

c) Die Therapie von Krankheitszuständen, die mit einer Überproduktion von Insulin einhergehen, könnte ergänzt bzw. ersetzt werden durch Insulinantagonisten, die auf der Basis der Komplementärpeptid-Theorie hergestellt werden (8).c) The therapy of disease states with an overproduction of Insulin, could be supplemented or replaced by Insulin antagonists based on complementary peptide theory be produced (8).

Problem:Problem:

Ziel unserer Überlegungen war, mit Hilfe der Komplementärpeptid-Theorie
a) ein antineoplastisches Mittel mit breitem Anwendungsspektrum zu entwickeln, das im Unterschied zu gängigen Therapieformen potentiell weniger Nebenwirkungen hat, eine höhere Spezifität aufweist und damit eher kausal wirkt. Zudem erscheint uns die Alternative der Komplementär­ peptide für den Patienten angemessener als die Alternative der Gentherapie, da erstere weniger stark in den Stoffwechsel der Zelle eingreift und damit potentiell weniger Nebenwirkungen entwickeln würde.The aim of our considerations was with the help of the complementary peptide theory
a) to develop an antineoplastic agent with a wide range of uses, which, in contrast to conventional forms of therapy, has fewer side effects, has a higher specificity and is therefore more causal. In addition, the alternative of complementary peptides seems to us more appropriate for the patient than the alternative of gene therapy, since the former interferes less with the cell metabolism and would therefore potentially have fewer side effects.

b) ein antihypertensives Mittel zu entwickeln, das eine Alternative zu den gängigen Substanzen, vor allem Kalziumantagonisten, darstellt und zwar entweder als Monotherapie oder in der Kombination mit anderen Mitteln. Dies könnte von Vorteil sein bei Patienten, die nicht optimal auf die verfügbaren Mittel ansprechen bzw. bei denen sich Therapierefraktärität einstellt. Letzteres ist gerade im Bereich von intensiv medizinisch betreuten Patienten oft zu beobachten.b) to develop an antihypertensive agent that is an alternative to the common substances, especially calcium channel blockers either as monotherapy or in combination with other agents. This could be beneficial for patients who are not optimal on the address available resources or where there is therapy refractory sets. The latter is particularly in the area of intensive medical care Watching patients often.

c) ein Mittel zu entwickeln, das man bei Krankheitszuständen einsetzt, die mit einer erhöhten Insulinproduktion einhergehen. Damit wäre eine alternative Behandlung von Insulinomen denkbar.c) to develop a means to be used for disease states which are associated with an increase in insulin production. That would be an alternative Treatment of insulinomas conceivable.

Lösung/Erreichte Vorteile/Weitere Ausgestaltung der Erfindung:Solution / advantages achieved / further embodiment of the invention:

a) Durch Anwendung der Komplementärpeptid-Theorie konnten wir die Struktur einer potentiell antineoplastischen Substanz (VPH) ableiten (2) (siehe Fig. 1). Diese ergab sich aus der Struktur des komplementären Peptids zum viralen Onkoprotein E7 des humanen Papillomvirus Typ 16, das z. B. bei der Entstehung von Zervixkarzinomen eine wesentliche Rolle spielt (5). Diese Struktur ist homolog zur Bindungsstelle dieses Virus auf dem Retinoblastom­ protein (RB), einem Tumorsuppressor-Genprodukt (13). Die Funktion dieses intrazellulären Proteins ist, das ungehemmte Wachstum von Zellen und damit die Entstehung von Tumoren zu unterbinden. Viren und andere zelluläre Proteine inaktivieren RB, indem sie eine Komplexbindung mit RB eingehen (5, 13). Die Gabe von VPH würde die Viren bzw. entsprechende zelluläre Proteine abfangen und dadurch die Kontrolle der Zellproliferation durch RB aufrechterhalten (2).a) Using the complementary peptide theory, we were able to derive the structure of a potentially antineoplastic substance (VPH) (2) (see Fig. 1). This resulted from the structure of the complementary peptide to the viral oncoprotein E7 of the human papilloma virus type 16, which, for. B. plays an essential role in the development of cervical cancer (5). This structure is homologous to the binding site of this virus on the retinoblastoma protein (RB), a tumor suppressor gene product (13). The function of this intracellular protein is to prevent the uninhibited growth of cells and thus the development of tumors. Viruses and other cellular proteins inactivate RB by complex binding with RB (5, 13). The administration of VPH would intercept the viruses or the corresponding cellular proteins and thereby maintain the control of cell proliferation by RB (2).

b) Durch Modifikationen der Struktur des Peptids, das komplementär zur Kalziumbindungsstelle auf dem Calmodulinmolekül ist (3), und Austestung der verschiedenen Varianten in Bindungsassays, die die Kompetition der einzelnen Peptide mit Kalziumionen um die gemeinsame Calmodulin­ bindungsstelle untersuchen würden, sowie in Bioassays, die die Kontraktion von Muskelzellen in Abhängigkeit von den kalziummimetischen Peptiden quantitativ erfassen, könnte schließlich die Peptidvariante gefunden werden, die zwar an die Calmodulinbindungsstelle bindet, aber keine kalzium­ ähnlichen Effekte mehr besitzt. Damit wäre eine neue Klasse von Kalzium­ antagonisten entdeckt, die möglicherweise effizienter wäre als die herkömmlichen Kalziumantagonisten. Diese neuen Kalziumantagonisten könnten sowohl in der antihypertensiven Behandlung als auch bei der Aufhebung der Resistenz bzw. der Refraktärität von Tumorzellen gegenüber Chemotherapeutika, die durch das sogenannte Multi-Drug-Resistance (MDR)-Gen-Produkt bewirkt wird, eingesetzt werden.b) By modifying the structure of the peptide that is complementary to Calcium binding site on the calmodulin molecule is (3), and testing of the different variants in binding assays that determine the competition of the individual peptides with calcium ions around the common calmodulin  would investigate the binding site, as well as in bioassays showing the contraction of muscle cells depending on the calcium mimetic peptides quantitatively, the peptide variant could eventually be found which binds to the calmodulin binding site, but not calcium has more similar effects. That would be a new class of calcium antagonists who might be more efficient than that conventional calcium channel blockers. These new calcium channel blockers could be used in both antihypertensive treatment and Cancellation of resistance or refractory to tumor cells Chemotherapy drugs through the so-called multi-drug resistance (MDR) gene product is used.

c) Die Suche nach dem Bindungsmotiv, das Viren bzw. bestimmte zelluläre Proteine verwenden, um an das Retinoblastomprotein (RB) zu binden und dieses somit zu inaktivieren, ergab, daß auch das pankreatische Hormon Insulin, genauer seine B-Kette, sowie die verwandten Wachsumsfaktoren insulin-like growth factor I und II (IGF-I und -II) dieses Motiv in ihrer Struktur beherbergen (6). Diese überraschende Entdeckung legt nahe, daß Insulin sowie IGF-I und -II möglicherweise an RB binden und dieses somit blockieren. Das Komplementärpeptid (hSNIB16-21[3′→5′]) (siehe Fig. 2) zum Bindungsmotiv im humanen Insulinmolekül könnte als ein spezifischer Insulinantagonist eingesetzt werden, z. B. bei Patienten mit Insulinomen, die mit einer erhöhten Insulinproduktion mit den entsprechenden negativen Stoffwechselerscheinungen einhergehen.c) The search for the binding motif that viruses or certain cellular proteins use to bind to the retinoblastoma protein (RB) and thus inactivate it showed that the pancreatic hormone insulin, more precisely its B chain, and the related ones Insulin-like growth factors I and II (IGF-I and -II) contain this motif in their structure (6). This surprising discovery suggests that insulin and IGF-I and -II may bind to RB and thus block it. The complementary peptide (hSNI B16-21 [3 '→ 5']) (see Fig. 2) for the binding motif in the human insulin molecule could be used as a specific insulin antagonist, e.g. B. in patients with insulinomas who are associated with an increased insulin production with the corresponding negative metabolic symptoms.

Für die Lösungen a), b) und c) gilt insgesamt folgendes:The following applies to solutions a), b) and c):

Die entsprechenden Komplementärpeptide müssen unter Berücksichtigung der entsprechenden biochemischen Herstellungsbedingungen produziert werden. Insbesondere müßte beachtet werden, daß diese Peptide unter Bedingungen der sogenannten Festphasenpeptidsynthese (solid phase peptide synthesis = SPPS) hergestellt werden (14, 15, 16).The corresponding complementary peptides must be considered the corresponding biochemical manufacturing conditions become. In particular, it should be noted that these peptides below Conditions of the so-called solid phase peptide synthesis (solid phase peptide synthesis = SPPS) (14, 15, 16).

Nachtrag:Addendum:

Vor kurzem wurde die Bedeutung von Medikamenten auf der Grundlage von Peptidstrukturen am Beispiel einer antihypertensiven, oral wirksamen Substanz (Renininhibitor) unterstrichen (17).Recently the importance of medication on the Basis of peptide structures using the example of an antihypertensive, orally active substance (renin inhibitor) underlined (17).

Beschreibung zweier Ausführungsbeispiele:Description of two exemplary embodiments:

Fig. 1: VPH
= NH2 - Leu αN-Me-Phe Tyr Lys αN-Me-Lys Val D-Tyr-COOH
= [αN-Me-Phe2, αN-Me-Lys5, D-Tyr7]-RB649-655 Fig. 1: VPH
= NH2 - Leu αN-Me-Phe Tyr Lys αN-Me-Lys Val D-Tyr-COOH
= [αN-Me-Phe 2 , αN-Me-Lys 5 , D-Tyr 7 ] -RB 649-655

Fig. 2: hSNIBB16-21[3′→5′]
= NH2- Leu Pro Thr His Asp Ala - COOH Fig. 2: hSNIB B16-21 [3 ′ → 5 ′]
= NH2-Leu Pro Thr His Asp Ala - COOH

Literaturverzeichnis:Bibliography:

1. Blalock, J. E. (1990). Complementarity of peptides specified by "sense" and "antisense" strands of DNA. Trends Biotechnol. 8, 140-144.1. Blalock, J.E. (1990). Complementarity of peptides specified by "sense" and "antisense" strands of DNA. Trends in biotechnology. 8, 140-144.

2. Wendtner, C. M. und Radulescu, R. T. (1992). Prediction of homologous binding sites on RB and p107 common for viral oncoproteins and cellular ligands. (submitted)2. Wendtner, C.M. and Radulescu, R.T. (1992). Prediction of homologous binding sites on RB and p107 common for viral oncoproteins and cellular ligands. (submitted)

3. Dillon, J., Woods, W. T., Guarcello, V., LeBoeuf, R. D. and Blalock, J. E. (1991). A peptide mimetic of calcium. Proc. Natl. Acad. Sci. USA 88, 9726- 9729.3. Dillon, J., Woods, W.T., Guarcello, V., LeBoeuf, R.D. and Blalock, J.E. (1991). A peptide mimetic of calcium. Proc. Natl. Acad. Sci. USA 88, 9726- 9729.

4. Radulescu, R.T. und Wendtner, C. M. (1992a). (unpublished observation) 4. Radulescu, R.T. and Wendtner, C.M. (1992a). (unpublished observation)  

5. Dyson, N., Howley, P. M., Münger K. and Harlow, E. (1989). The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science 243, 934-937.5. Dyson, N., Howley, P.M., Münger K. and Harlow, E. (1989). The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science 243, 934-937.

6. Radulescu, R. T. und Wendtner, C. M. (1992). Insulin B-chain: Identification of core binding motif essential for complex formation with retinoblastoma protein. (submitted)6. Radulescu, R. T. and Wendtner, C. M. (1992). Insulin B-chain: identification of core binding motif essential for complex formation with retinoblastoma protein. (submitted)

7. Defeo-Jones, D., Huang, P.S., Jones R.E., Haskell, K.M., Vuocolo, G.A., Hanobik, M.G., Huber, H.E. and Oliff, A.(1991). Cloning of cDNAs for cellular proteins that bind to the retinoblastoma gene produkt. Nature 352, 251-254.7. Defeo-Jones, D., Huang, P.S., Jones R.E., Haskell, K.M., Vuocolo, G.A., Hanobik, M.G., Huber, H.E. and Oliff, A. (1991). Cloning of cDNAs for cellular proteins that bind to the retinoblastoma gene product. Nature 352, 251-254.

8. Radulescu, R. T. und Wendtner, C. M. (1992b). (unpublished observation)8. Radulescu, R. T. and Wendtner, C. M. (1992b). (unpublished observation)

9. Culver, K. W., Ram, Z., Wallbridge, S., Ishii, H., Oldfield, E. H. and Blaese, R. M. (1992). In vivo gene transfer with retroviral vector-producer cells for treatment of experimental brain tumors. Science 256, 1550-1552.9. Culver, K.W., Ram, Z., Wallbridge, S., Ishii, H., Oldfield, E.H. and Blaese, R. M. (1992). In vivo gene transfer with retroviral vector-producer cells for treatment of experimental brain tumors. Science 256, 1550-1552.

10. Pastan, I. and Fitzgerald, D. (1991). Recombinant toxins for cancer treatment. Science 254, 1173-1177.10. Pastan, I. and Fitzgerald, D. (1991). Recombinant toxins for cancer treatment. Science 254, 1173-1177.

11. Rosenberg, S. A. (1988). Immunol. Today 9, 58.11. Rosenberg, S.A. (1988). Immunol. Today 9, 58.

12. Ward, E. S., Güssow, D., Griffiths, A. D., Jones, P. T. and Winter, G. (1989). Binding activities of a repertoire of single immunoglobin variable domains secreted form Escherichia coli. Nature 341, 544-546.12. Ward, E.S., Gussow, D., Griffiths, A.D. Jones, P.T. and Winter, G. (1989). Binding activities of a repertoire of single immunoglobin variable domains secreted form Escherichia coli. Nature 341, 544-546.

13. Chellappan, S:, Kraus, V. B., Kroger, B., Munger, K., Howley, P. M., Phelps, W. C. and Nevins, J. R. (1992). Adenovirus E1A, simian virus 40 tumor antigen, and human papillomavirus E7 protein share the capacity to disrupt the interaction between transcription factor E2F and the retinoblastoma gene product. Proc. Natl. Acad. Sci. USA 89, 4549-4553.13. Chellappan, S :, Kraus, V.B., Kroger, B., Munger, K., Howley, P.M., Phelps, W.C. and Nevins, J.R. (1992). Adenovirus E1A, simian virus 40 tumor antigen, and human papillomavirus E7 protein share the capacity to disrupt  the interaction between transcription factor E2F and the retinoblastoma gene product. Proc. Natl. Acad. Sci. USA 89, 4549-4553.

14. Merrifield, R. B. (1963). Solid phase peptide synthesis I. The synthesis of a tetrapeptide. J. Am. Chem. Soc. 85, 2149-2154.14. Merrifield, R.B. (1963). Solid phase peptide synthesis I. The synthesis of a tetrapeptides. J. Am. Chem. Soc. 85, 2149-2154.

15. Shai, Y., Brunck, T. K. and Chaiken, I. M. (1989). Antisense peptide recognition of sense peptides: sequence simplification and evaluation of forces underlying the interaction. Biochemistry 28, 8804-8811.15. Shai, Y., Brunck, T.K. and Chaiken, I.M. (1989). Antisense peptides recognition of sense peptides: sequence simplification and evaluation of forces underlying the interaction. Biochemistry 28, 8804-8811.

16. Grant, G. A.(1992). Synthetic peptides. A user′s guide. W. H. Freeman & Co., New York.16. Grant, G.A. (1992). Synthetic peptides. A user’s guide. W. H. Freeman & Co., New York.

17. Kleinert, H. D., Rosenberg, S. H., Baker, W. R., Stein, H. H., Klinghofer, V., Barlow, J. Spina, K., Polakowski, J., Kovar, P., Cohen, J. and Denissen, J. (1992). Discovery of a peptide-based renin inhibitor with oral bioavailability and efficacy. Science 257, 1940-1943.17. Kleinert, H.D., Rosenberg, S.H., Baker, W.R., Stein, H.H., Klinghofer, V., Barlow, J. Spina, K., Polakowski, J., Kovar, P., Cohen, J. and Denissen, J. (1992). Discovery of a peptide-based renin inhibitor with oral bioavailability and efficacy. Science 257, 1940-1943.

Claims (2)

Unsere Patentansprüche beziehen sich auf die Anwendung der Komplementärpeptid-Theorie im biomedizinischen Bereich, genauer auf die Entwicklung von Medikamenten im Bereich der Onkologie und Kardiologie. Die Komplementärpeptid-Theorie postuliert, daß Peptide, die durch komplementäre DNA-Stränge kodiert werden, interagieren (1). Daraus ergibt sich, daß beispielsweise Hormone und ihre Rezeptoren von komplementären DNA- Sequenzen kodiert werden, aber auch, daß man durch Kenntnis der DNA-Sequenz eines bestimmten Proteins ein dazu komplementäres Peptid vorhersagen und entwerfen kann (1).Our claims relate to the application of the Complementary peptide theory in the biomedical field, more precisely on that Development of drugs in the field of oncology and cardiology. The Complementary peptide theory postulates that peptides are complementary DNA strands are encoded, interact (1). It follows that for example hormones and their receptors from complementary DNA Sequences are encoded, but also that you know by knowing the DNA sequence predict a peptide complementary to a particular protein and can design (1). Spezifisch geschützt werden soll der von uns gleichermaßen geteilte Erstanspruch
  • 1. auf die Entwicklung einer Struktur einer potentiell antineoplastischen Substanz (VPH) (2) (siehe Fig. 1);
  • 2. auf die Idee, durch Variationen der Primärstruktur eines kalzium­ mimetischen Peptids (3) ein potentiell antihypertensives Mittel zu entwickeln (4). Dieses Mittel könnte auch bei der Behandlung von Tumoren eingesetzt werden, indem es das sogenannte Multi-Drug- Resistance (MDR)-Gen-Produkt inaktiviert;
  • 3. a) auf die Entdeckung, daß Insulin und insulin-like growth factor-I und -II (IGF-I und -II) das Bindungsmotiv LXCXE (5), das virale Onkoproteine sowie entsprechende Zellproteine zur Bindung und Inaktivierung von Retinoblastomprotein (RB) verwenden, in ihrer Struktur enthalten (6);
  • b) auf den Nachweis, daß die Komplementärpeptide zu Insulin und IGF-1 und -II strukturell ähnlich bzw. identisch zu den Komplementärpeptiden des viralen Onkoproteins E7 und der RB-bindenden Proteine-1 und -2 (RBP-1 und -2) (7) sind und damit eine Kompetition um eine gemeinsame RB- Bindungsstelle, und zwar RB649-654, nahelegen (6);
  • c) auf die Idee, das Peptid hSNIB16-21[3′→5′] (siehe Fig. 2) als potentielles Agens bei der Behandlung von Krankheitszuständen einschließlich Tumoren, die mit einer Insulinüberproduktion einhergehen, einzusetzen (8).
The initial claim, which we share equally, is to be specifically protected
  • 1. on the development of a structure of a potentially antineoplastic substance (VPH) (2) (see FIG. 1);
  • 2. The idea of developing a potentially antihypertensive agent by varying the primary structure of a calcium mimetic peptide (3) (4). This agent could also be used in the treatment of tumors by inactivating the so-called multi-drug resistance (MDR) gene product;
  • 3. a) on the discovery that insulin and insulin-like growth factor-I and -II (IGF-I and -II) the binding motif LXCXE (5), the viral oncoproteins and corresponding cell proteins for binding and inactivating retinoblastoma protein (RB ) use, included in their structure (6);
  • b) on the proof that the complementary peptides to insulin and IGF-1 and -II are structurally similar or identical to the complementary peptides of the viral oncoprotein E7 and the RB-binding proteins-1 and -2 (RBP-1 and -2) ( 7) and thus suggest competition for a common RB binding site, namely RB 649-654 (6);
  • c) on the idea of using the peptide hSNI B16-21 [3 ′ → 5 ′] (see FIG. 2) as a potential agent in the treatment of disease states, including tumors, which are associated with insulin overproduction (8).
DE19924237129 1992-11-03 1992-11-03 Application of complementary peptide(s) in oncology and cardiology - pref. using peptide(s) complementary to human papilloma virus type 16 onco-protein E7, binding to retino-blastoma proteins Withdrawn DE4237129A1 (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997035873A2 (en) * 1996-03-26 1997-10-02 Radulescu Razvan T Peptides with antiproliferative properties
EP0902088A2 (en) * 1996-03-26 1999-03-17 Razvan T. Radulescu Peptides with antiproliferative properties
WO2000053189A1 (en) * 1999-03-10 2000-09-14 The Uab Research Foundation Inhibitors of calcium influx factor synthesis and/or action and uses thereof

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997035873A2 (en) * 1996-03-26 1997-10-02 Radulescu Razvan T Peptides with antiproliferative properties
WO1997035873A3 (en) * 1996-03-26 1997-12-31 Razvan T Radulescu Peptides with antiproliferative properties
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
AU727662B2 (en) * 1996-03-26 2000-12-21 Razvan T. Radulescu Peptides having antiproliferative properties
WO2000053189A1 (en) * 1999-03-10 2000-09-14 The Uab Research Foundation Inhibitors of calcium influx factor synthesis and/or action and uses thereof

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