WO1997033622B1 - Delivery of nucleic acids by porphyrins - Google Patents
Delivery of nucleic acids by porphyrinsInfo
- Publication number
- WO1997033622B1 WO1997033622B1 PCT/US1997/004000 US9704000W WO9733622B1 WO 1997033622 B1 WO1997033622 B1 WO 1997033622B1 US 9704000 W US9704000 W US 9704000W WO 9733622 B1 WO9733622 B1 WO 9733622B1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- poφhyrin
- oligonucleotide
- composition
- macrocycle
- Prior art date
Links
- 150000004032 porphyrins Chemical class 0.000 title claims abstract 8
- 108020004707 nucleic acids Proteins 0.000 title claims abstract 7
- 102000039446 nucleic acids Human genes 0.000 title claims abstract 7
- 150000007523 nucleic acids Chemical class 0.000 title claims abstract 7
- 150000001875 compounds Chemical class 0.000 claims abstract 23
- 108091034117 Oligonucleotide Proteins 0.000 claims abstract 19
- 238000000034 method Methods 0.000 claims abstract 19
- 239000000203 mixture Substances 0.000 claims abstract 14
- 150000002678 macrocyclic compounds Chemical class 0.000 claims abstract 9
- -1 EGSs Proteins 0.000 claims abstract 6
- 108090000623 proteins and genes Proteins 0.000 claims abstract 6
- 102000004169 proteins and genes Human genes 0.000 claims abstract 6
- 230000000840 anti-viral effect Effects 0.000 claims abstract 4
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract 4
- 102000053642 Catalytic RNA Human genes 0.000 claims abstract 3
- 108090000994 Catalytic RNA Proteins 0.000 claims abstract 3
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 claims abstract 3
- 230000000692 anti-sense effect Effects 0.000 claims abstract 3
- 230000000694 effects Effects 0.000 claims abstract 3
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract 3
- 108091092562 ribozyme Proteins 0.000 claims abstract 3
- 208000002672 hepatitis B Diseases 0.000 claims 4
- 102000004167 Ribonuclease P Human genes 0.000 claims 3
- 108090000621 Ribonuclease P Proteins 0.000 claims 3
- ZNEOHLHCKGUAEB-UHFFFAOYSA-N trimethylphenylammonium Chemical compound C[N+](C)(C)C1=CC=CC=C1 ZNEOHLHCKGUAEB-UHFFFAOYSA-N 0.000 claims 3
- 108091023037 Aptamer Proteins 0.000 claims 2
- 108700005077 Viral Genes Proteins 0.000 claims 2
- 239000003153 chemical reaction reagent Substances 0.000 claims 2
- 150000004676 glycans Chemical class 0.000 claims 2
- 239000013612 plasmid Substances 0.000 claims 2
- 229920001282 polysaccharide Polymers 0.000 claims 2
- 239000005017 polysaccharide Substances 0.000 claims 2
- 239000013603 viral vector Substances 0.000 claims 2
- 230000003612 virological effect Effects 0.000 claims 2
- 150000008574 D-amino acids Chemical class 0.000 claims 1
- 206010019799 Hepatitis viral Diseases 0.000 claims 1
- 150000008575 L-amino acids Chemical class 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 claims 1
- LGAILEFNHXWAJP-BMEPFDOTSA-N macrocycle Chemical group N([C@H]1[C@@H](C)CC)C(=O)C(N=2)=CSC=2CNC(=O)C(=C(O2)C)N=C2[C@H]([C@@H](C)CC)NC(=O)C2=CSC1=N2 LGAILEFNHXWAJP-BMEPFDOTSA-N 0.000 claims 1
- 230000010076 replication Effects 0.000 claims 1
- 201000001862 viral hepatitis Diseases 0.000 claims 1
- 210000004027 cell Anatomy 0.000 abstract 2
- 241000700605 Viruses Species 0.000 abstract 1
- 150000001720 carbohydrates Chemical class 0.000 abstract 1
- 208000006454 hepatitis Diseases 0.000 abstract 1
- 231100000283 hepatitis Toxicity 0.000 abstract 1
- 210000003494 hepatocyte Anatomy 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract 1
Abstract
Efficient methods and compositions are provided for the targeted delivery of effective concentrations of compounds, including nucleic acid molecules and oligonucleotides such as EGSs, ribozymes and antisense, proteins, peptides, carbohydrate, and synthetic organic and inorganic molecules, or combinations thereof, to cells, especially hepatocytes. In the preferred embodiment, the compound is a negatively charged oligonucleotide which binds in a stoichiometric ratio to a water soluble, positively charged macrocycle such as a porphyrin, which targets and protects the oligonucleotide. The porphyrin protects the compound to be delivered and delivers the compound preferentially to certain cells and tissue types. In another embodiment, the porphyrin has anti-human hepatitis virus activity, when administered alone, which is significantly enhanced when in combination with an antiviral compound, especially an oligonucleotide.
Claims
1. A method for delivering a compound having a net negative charge to cells comprising mixing the compound with a macrocycle having a net positive charge in an amount effective to enhance delivery of the compound to cells binding the macrocycle, wherein the compound and the macrocycle are ionically bound together; and delivering the compound-macrocycle composition to the cells.
2. The method of claim 1 wherein the compound is selected from the group consisting of proteins, peptides, oligonucleotides, biologically active synthetic organic molecules, polysaccharides, and diagnostic reagents, wherein the compound has a net negative charge at physiological pH.
3. The method of claim 2 wherein the compound is an oligonucleotide.
4. The method of claim 3 wherein the oligonucleotide is selected from the group consisting of antisense nucleic acid molecules, ribozymes, external guide sequences for RNase P, aptamers, triplex molecules, genes, viral vectors, plasmids, and protein encoding sequences.
5. The method of claim 1 wherein the macrocycle is a porphyrin.
6. The method of claim 1 wherein the porphyrin is selected from the group consisting of natural porphyrins, natural phthalocyanins, synthetic porphyrins, synthetic phthalocyanins, and conjugates thereof.
7. The method of claim 1 wherein the compound is an oligonucleotide and the macrocycle is a poφhyrin further comprising mixing the poφhyrin and oligonucleotide in a ratio resulting in all of the oligonucleotide binding to the poφhyrin.
8. The method of claim 7 wherein the poφhyrin has antiviral activity.
9. The method of claim 8 wherein the poφhyrin has anti-hepatitis B activity.
42
10. The method of claim 9 wherein the poφhyrin is tetra meso (n- methyl 4-pyridyl) poφhine (TMP) or meso tetra (trimethyl anilinium) poφhine (TMA).
11. The method of claim 1 wherein the compound has anti-viral activity.
12. The method of claim 11 wherein the compound is an oligonucleotide targeted to viral nucleic acid.
13. The method of claim 12 wherein the viral nucleic acid is hepatitis viral nucleic acid.
14. A method for inhibiting hepatitis B infection of cells comprising administering to the cells an effective amount of a poφhyrin to inhibit replication of hepatitis B in the cells.
15. The method of claim 14 wherein the poφhyrin is selected from the group consisting of natural poφhyrins, natural phthalocyanins, synthetic poφhyrins, synthetic phthalocyanins, and conjugates thereof.
16. The method of claim 15 wherein the poφhyrin is a synthetic poφhyrin.
17. The method of claim 16 wherein the poφhyrin is tetra meso (n- methyl 4-pyridyl) poφhine (TMP) or meso tetra (trimethyl anilinium) poφhine (TMA).
18. The method of claim 14 wherein the poφhyrin is administered to a patient in need of treatment thereof.
19. A composition for delivering a compound having a net negative charge to cells comprising the compound ionically bound to a macrocycle having a net positive charge selected from the group consisting of natural poφhyrins, natural phthalocyanins, synthetic poφhyrins, synthetic phthalocyanins, and conjugates thereof, in an amount effective to enhance delivery of the compound to cells preferentially binding the macrocycle.
20. The composition of claim 19 wherein the compound is selected from the group consisting of proteins, peptides, oligonucleotides, biologically
43 active synthetic organic molecules, polysaccharides, and diagnostic reagents, wherein the compound has a net negative charge at physiological pH.
21. The composition of claim 20 wherein the compound is an oligonucleotide.
22. The composition of claim 21 wherein the oligonucleotide is selected from the group consisting of antisense nucleic acid molecules, ribozymes, external guide sequences for RNase P, aptamers, triplex molecules, genes, viral vectors, plasmids, and protein encoding sequences.
23. The composition of claim 19 wherein the macrocycle is a poφhyrin selected from the group consisting of natural poφhyrins, natural phthalocyanins, synthetic poφhyrins, synthetic phthalocyanins, and conjugates thereof.
24. The composition of claim 19 wherein the compound is an oligonucleotide and the macrocycle is a poφhyrin further comprising mixing the poφhyrin and oligonucleotide in a ratio resulting in all of the oligonucleotide binding to the poφhyrin.
25. The composition of claim 23 wherein the poφhyrin has antiviral activity.
26. The composition of claim 25 wherein the poφhyrin has anti- hepatitis B activity.
27. The composition of claim 26 wherein the poφhyrin is tetra meso (n-methyl 4-pyridyl) poφhine (TMP) or meso tetra (trimethyl anilinium) poφhine (TMA).
28. The composition of claim 26 wherein the poφhyrin is bound to oligonucleotide to be delivered.
29. The composition of claim 28 wherein the oligonucleotide is an external guide sequence for RNase P.
30. The composition of claim 19 wherein the compound is a protein or a peptide comprising L-amino acids or D-amino acids with a net negative charge.
44
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP97915946A EP0894011A2 (en) | 1996-03-14 | 1997-03-14 | Delivery of nucleic acids by porphyrins |
| AU23244/97A AU2324497A (en) | 1996-03-14 | 1997-03-14 | Delivery of nucleic acids by porphyrins |
| US08/912,378 US6610478B1 (en) | 1996-08-16 | 1997-08-15 | Phenotypic conversion of cells mediated by external guide sequences |
| US09/627,562 US6558954B1 (en) | 1996-08-16 | 2000-07-28 | Phenotypic conversion of cells mediated by external guide sequences |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/616,141 US6620805B1 (en) | 1996-03-14 | 1996-03-14 | Delivery of nucleic acids by porphyrins |
| US08/616,141 | 1996-03-14 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US08/912,378 Continuation-In-Part US6610478B1 (en) | 1996-08-16 | 1997-08-15 | Phenotypic conversion of cells mediated by external guide sequences |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| WO1997033622A2 WO1997033622A2 (en) | 1997-09-18 |
| WO1997033622A3 WO1997033622A3 (en) | 1998-02-26 |
| WO1997033622B1 true WO1997033622B1 (en) | 1998-04-16 |
Family
ID=24468218
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1997/004000 WO1997033622A2 (en) | 1996-03-14 | 1997-03-14 | Delivery of nucleic acids by porphyrins |
Country Status (4)
| Country | Link |
|---|---|
| US (1) | US6620805B1 (en) |
| EP (1) | EP0894011A2 (en) |
| AU (1) | AU2324497A (en) |
| WO (1) | WO1997033622A2 (en) |
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| US6207646B1 (en) | 1994-07-15 | 2001-03-27 | University Of Iowa Research Foundation | Immunostimulatory nucleic acid molecules |
| US20030026782A1 (en) * | 1995-02-07 | 2003-02-06 | Arthur M. Krieg | Immunomodulatory oligonucleotides |
| WO1998006837A1 (en) * | 1996-08-16 | 1998-02-19 | Yale University | Phenotypic conversion of drug-resistant bacteria to drug-sensitivity |
| US6610478B1 (en) | 1996-08-16 | 2003-08-26 | Yale University | Phenotypic conversion of cells mediated by external guide sequences |
| WO1998006440A2 (en) * | 1996-08-16 | 1998-02-19 | Innovir Laboratories, Inc. | Phenotypic conversion of cells mediated by external guide sequences |
| EP0855184A1 (en) * | 1997-01-23 | 1998-07-29 | Grayson B. Dr. Lipford | Pharmaceutical composition comprising a polynucleotide and an antigen especially for vaccination |
| US6406705B1 (en) | 1997-03-10 | 2002-06-18 | University Of Iowa Research Foundation | Use of nucleic acids containing unmethylated CpG dinucleotide as an adjuvant |
| US20020155999A1 (en) * | 1998-04-30 | 2002-10-24 | Han In Suk | Method of using a porphyrin-like molecule conjugated with an anti-cancer drug for the treatment of cancer |
| US20030022854A1 (en) | 1998-06-25 | 2003-01-30 | Dow Steven W. | Vaccines using nucleic acid-lipid complexes |
| BRPI0215088B1 (en) * | 2001-12-20 | 2015-12-22 | Sasol Tech Pty Ltd | trimerization catalyst system and process for olefin oligomerization |
| US20050048641A1 (en) * | 2002-11-26 | 2005-03-03 | Medtronic, Inc. | System and method for delivering polynucleotides to the central nervous system |
| JP2006512927A (en) | 2002-12-11 | 2006-04-20 | コーリー ファーマシューティカル グループ，インコーポレイテッド | 5 'CPG nucleic acids and methods of use thereof |
| GB2397067B (en) * | 2002-12-23 | 2005-05-11 | Destiny Pharma Ltd | Porphin & azaporphin derivatives with at least one cationic-nitrogen-containing meso-substituent for use in photodynamic therapy & in vitro sterilisation |
| US7109173B1 (en) | 2004-03-16 | 2006-09-19 | Wilbert Gamble | Transport of nucleotides, oligonucleotides and polynucleotides into the cytoplasm and nucleus of cells by peptides |
| GB2415372A (en) | 2004-06-23 | 2005-12-28 | Destiny Pharma Ltd | Non photodynamical or sonodynamical antimicrobial use of porphyrins and azaporphyrins containing at least one cationic-nitrogen-containing substituent |
| US20070036740A1 (en) * | 2004-10-06 | 2007-02-15 | Reed Kenneth C | Modulation of hair growth |
| EP1807514A1 (en) * | 2004-10-22 | 2007-07-18 | Benitec, Inc. | Therapeutic rnai agents for treating psoriasis |
| EP1838853A2 (en) * | 2005-01-06 | 2007-10-03 | Benitec, Inc. | Rnai agents for maintenance of stem cells |
| US20070128116A1 (en) * | 2005-07-27 | 2007-06-07 | Wang Zheng J | Multifunctional core for molecular imaging and targeted delivery of macromolecules and drugs |
| GB0519169D0 (en) * | 2005-09-21 | 2005-10-26 | Leuven K U Res & Dev | Novel anti-viral strategy |
| EP1948674A4 (en) | 2005-11-02 | 2009-02-04 | Protiva Biotherapeutics Inc | Modified sirna molecules and uses thereof |
| CA2710713C (en) | 2007-12-27 | 2017-09-19 | Protiva Biotherapeutics, Inc. | Silencing of polo-like kinase expression using interfering rna |
| WO2009129319A2 (en) | 2008-04-15 | 2009-10-22 | Protiva Biotherapeutics, Inc. | Silencing of csn5 gene expression using interfering rna |
| JP2013530187A (en) | 2010-06-17 | 2013-07-25 | ザ ユナイテッド ステイツ オブ アメリカ アズ リプレゼンティッド バイ ザ シークレタリー デパートメント オブ ヘルス アンド ヒューマン サービシーズ | Compositions and methods for treating inflammatory diseases. |
| WO2013075132A1 (en) | 2011-11-17 | 2013-05-23 | The United States Of America, As Represented By The Secretary, Department Of Health & Human Services | Therapeutic rna switches compositions and methods of use |
| US9035039B2 (en) | 2011-12-22 | 2015-05-19 | Protiva Biotherapeutics, Inc. | Compositions and methods for silencing SMAD4 |
| EP2817327A1 (en) | 2012-02-21 | 2014-12-31 | Institut National de la Sante et de la Recherche Medicale (INSERM) | Tim receptors as virus entry cofactors |
| EP2817328A1 (en) | 2012-02-21 | 2014-12-31 | Institut National de la Santé et de la Recherche Médicale | Tam receptors as virus entry cofactors |
| CN104736563A (en) | 2012-07-27 | 2015-06-24 | 国家健康与医学研究院 | Cd147 as receptor for pilus-mediated adhesion of meningococci to vascular endothelia |
| WO2015019548A1 (en) * | 2013-08-05 | 2015-02-12 | パナソニック株式会社 | Method for inhibiting dna degradation reaction, and dna degradation reaction inhibitor |
| JP2017536092A (en) | 2014-10-02 | 2017-12-07 | プロティバ バイオセラピューティクス インコーポレイテッド | Compositions and methods for silencing gene expression of hepatitis B virus |
| US20180245074A1 (en) | 2015-06-04 | 2018-08-30 | Protiva Biotherapeutics, Inc. | Treating hepatitis b virus infection using crispr |
| CN108350455A (en) | 2015-07-29 | 2018-07-31 | 阿布特斯生物制药公司 | Composition for making hepatitis B virus silenced gene expression and method |
| WO2018038155A1 (en) * | 2016-08-23 | 2018-03-01 | 国立大学法人東京大学 | Micelle and use of same |
| US20200352913A1 (en) | 2017-11-23 | 2020-11-12 | INSERM (Institut National de la Santé et de la Recherche Médicale) | New method for treating dengue virus infection |
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-
1996
- 1996-03-14 US US08/616,141 patent/US6620805B1/en not_active Expired - Lifetime
-
1997
- 1997-03-14 EP EP97915946A patent/EP0894011A2/en not_active Withdrawn
- 1997-03-14 WO PCT/US1997/004000 patent/WO1997033622A2/en not_active Application Discontinuation
- 1997-03-14 AU AU23244/97A patent/AU2324497A/en not_active Abandoned
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