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WO1996016976A1 - Oligonucleotide anti-sens et agent cancerostatique contenant cet oligonucleotide - Google Patents

Oligonucleotide anti-sens et agent cancerostatique contenant cet oligonucleotide Download PDF

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Publication number
WO1996016976A1
WO1996016976A1 PCT/JP1995/002452 JP9502452W WO9616976A1 WO 1996016976 A1 WO1996016976 A1 WO 1996016976A1 JP 9502452 W JP9502452 W JP 9502452W WO 9616976 A1 WO9616976 A1 WO 9616976A1
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WIPO (PCT)
Prior art keywords
seq
sequence
oligonucleotide
nucleotide sequence
protein kinase
Prior art date
Application number
PCT/JP1995/002452
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English (en)
Japanese (ja)
Inventor
Masahiko Tsuchiya
Timothy G. Geiser
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Pola Chemical Industries Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pola Chemical Industries Inc. filed Critical Pola Chemical Industries Inc.
Publication of WO1996016976A1 publication Critical patent/WO1996016976A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1137—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/31—Chemical structure of the backbone
    • C12N2310/314—Phosphoramidates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/31—Chemical structure of the backbone
    • C12N2310/314—Phosphoramidates
    • C12N2310/3145—Phosphoramidates with the nitrogen in 3' or 5'-position
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/32—Chemical structure of the sugar
    • C12N2310/322—2'-R Modification

Definitions

  • the present invention relates to anticancer agents comprising antisense oligonucleotides against human protein kinases, particularly human protein kinases A-RI, anticancer agents comprising the antisense oligonucleotides, and anticancer agents comprising the antisense oligonucleotides.
  • the present invention relates to a pharmaceutical composition containing an anticancer agent.
  • Prior Art Cancer has long been known as an incurable disease, but it has not changed much to date. It is a so-called rebellious molecule, in which cancer cells are derived from the organism itself. The basic physiological mechanism is not much different from normal cells, so if you try to kill cancer cells with anticancer drugs or the like, normal cells It also causes side effects.
  • oligonucleotide having a nucleotide sequence complementary to a part of the gene, so that it is called a cancer-related gene.
  • Antisense technology for covering has been devised, and various studies have been made on this technology. Since this antisense oligonucleotide inhibits gene expression indiscriminately for both cancer cells and normal cells, it is important to know what kind of gene expression is to be suppressed. I have.
  • the present inventors have conducted intensive studies in order to increase the anti-cancer effect of the antisense oligonucleotide on the protein kinase Ait gene to a practically usable level. As a result, they found that the anticancer effect was significantly increased and completed the invention.
  • the present invention relates to an oligonucleotide having at least a part of a nucleotide sequence complementary to all or a part of the sequence of the human protein kinase A gene and having a structure represented by the general formula (I). It is.
  • n represents an integer
  • R represents a hydrogen atom or a hydroxyl group
  • B represents a nucleic acid base.
  • the human protein kinase A gene the human protein kinase A Sequences encoding tree portions or portions thereof are included. Further, the regulatory portion includes RI- ⁇ .
  • the present invention provides an anticancer drug comprising the above-mentioned oligonucleotide, and a pharmaceutical composition for treating cancer, comprising at least one selected from the anticancer drugs.
  • antisense oligonucleotide refers to an oligonucleotide that suppresses the expression of its gene by hybridizing to a gene or mRNA, and the coding strand of gene DNA (( +) Strand) or an oligonucleotide having a nucleotide sequence complementary to the mRNA, as well as an oligonucleotide having a nucleotide sequence complementary to the non-coding strand ((-) strand).
  • the antisense oligonucleotide of the present invention has a nucleotide sequence at least partially complementary to all or a part of the sequence of human protein kinase A ⁇ gene. Oligonucleotide. As a part of the sequence of the human protein kinase A gene, a sequence encoding the regulatory part of human protein kinase A or a part thereof can be mentioned. Further, the regulatory part includes RI-na.
  • the antisense oligonucleotide of the present invention has a base sequence as described above, and the bonding mode between the nucleotides constituting the oligonucleotide is a 3′-amino group represented by the general formula (I). This is due to the phosphoramidate bond to which the 5 'phosphate group is bound (hereinafter simply referred to as "phosphoraamidate bond").
  • the length of the oligonucleotide chain is not particularly limited as long as the specificity for the protein kinase A gene is maintained.
  • the preferred length is 9 to 40 in terms of the number of bases. This is because if it is less than 9, the specificity for the gene may be low and the anticancer effect may not be sufficiently exerted, and if it exceeds 40, it will be extremely difficult to synthesize by controlling the nucleotide sequence.
  • a more preferable chain length is one having a base number of 15 to 24, which has the best balance between effects and economics.
  • the antisense oligonucleotide of the present invention is not particularly limited as long as it is a nucleic acid having a sequence complementary to a gene involved in the biosynthesis of protein kinase A-RIa. That is, as long as the bond between nucleotides is a phosphoramidate bond, even if the oligonucleotide is of the DNA type (R is a hydrogen atom in the general formula (I)), the RNA type (R in the general formula (I)) May be a hydroxyl group).
  • sequence of the antisense oligonucleotide to protein kinase A-RI ⁇ is a sequence substantially complementary to a part of the base sequence of the coding or non-coding chain of the protein kinase ⁇ -RI ⁇ gene, in other words, non-coding. If the sequence is substantially identical to a part of the nucleotide sequence of the protein or the code chain, it is expected that the biosynthesis of protein kinase ⁇ -RI ⁇ can be suppressed.
  • the above effect can be expected at any site in the gene, but when the expression of protein kinase A-RI ⁇ activity is more completely suppressed, From this point of view, it is preferably a part of the sequence consisting of 300 nucleotides from the initiation codon to the 100th codon, at the 5 'end of the coding strand of the gene. 300 nucleotides in the coding region of this protein kinase ⁇ —RI ⁇ ⁇ gene The sequence of the reotide is shown in SEQ ID NO: 1.
  • the antisense sequence corresponding to this sequence is shown in SEQ ID NO: 6.
  • SEQ ID NO: 6 the relationship between the sequence shown in SEQ ID NO: 1 and the sequence shown in SEQ ID NO: 6 is complementary, and anticancer activity can be expected with antisense oligonucleotides for either strand of the gene.
  • nucleotide sequence shown in SEQ ID NO: 1 or 6 it is preferable that the nucleotide sequence is 5 'end in SEQ ID NO: 1 and 3' end in SEQ ID NO: 6.
  • substantially complementary does not require that all the nucleotides in the oligonucleotide be complementary to the protein kinase A gene, and that the oligonucleotide is the gene DNA or m. It means that it only has to hybridize to the corresponding site of RNA and be complementary enough to inhibit transcription or translation. Therefore, some nucleotides in the nucleotide chain may be substituted, deleted or inserted as long as specific hybridization is not inhibited under physiological conditions.
  • nucleotides that can be replaced in an antisense oligonucleotide vary depending on the length and sequence of the oligonucleotide, but generally the effects of substitution, deletion and insertion are less near the ends of the oligonucleotide than inside. , AT (or AU) base pairs are less affected by substitution than GC base pairs.
  • Methods for calculating the hybridization intensity of nucleic acids are known, and those skilled in the art may modify some of the sequences based on the sequences shown in SEQ ID NOs: 1 and 6 so that hybridization under physiological conditions is not impaired. It is easy to do.
  • those having a homology of 90% or more to the protein kinase A gene can be expected to have some expected effect and can be defined as substantially complementary. . Further, even if an oligonucleotide having a non-specific sequence is added to the 5 'end or 3' end of such an oligonucleotide, it is not substantially affected.
  • the type of nucleotides constituting the antisense oligonucleotide of the present invention may be a DNA-comprising nucleotide analog in which the base is thymine, adenine, cytosine, or guanine and the sugar is deoxyribose.
  • RNA-constituting nucleotide analogs containing ribonucleic acid, cytosine, and guanine and sugar as ribose may be used.
  • non-specific hydrogen bonding with other bases such as inosine is possible. It may contain a functional base.
  • Most preferred are oligonucleotides of nucleotide analogs that are complementary to the nucleotide sequence of SEQ ID NO: 1.
  • the antisense oligonucleotide sequence to protein kinase A-RI ⁇ has a sequence complementary to a part of the base sequence shown in SEQ ID NO: 1, that is, a sequence identical to a part of the sequence shown in SEQ ID NO: 6.
  • Specific examples include oligonucleotides having the nucleotide sequences shown in SEQ ID NOs: 2, 3, 4, and 5.
  • a sequence complementary to a part of the base sequence shown in SEQ ID NO: 6, that is, a sequence having the same sequence as a part of the sequence shown in SEQ ID NO: 1 is specifically shown in SEQ ID NOs: 7, 8, and 9.
  • oligonucleotides The positions of these oligonucleotides on the sequence shown in SEQ ID NO: 1 or 6 are shown below.
  • SEQ ID NO: 2 Nucleotide number 280 to 300 of SEQ ID NO: 6
  • SEQ ID NO: 3 Nucleotide numbers 46 to 57 of SEQ ID NO: 6
  • SEQ ID NO: 4 Nucleotide number of SEQ ID NO: 6 1 4 8 to 16 5
  • SEQ ID NO: 5 Nucleotide number of SEQ ID NO: 6 from 250 to 2 79
  • SEQ ID NO: 7 Nucleotide numbers 1 to 21 of SEQ ID NO: 1
  • SEQ ID NO: 8 Nucleotide number 2 4 4 to 25 5 of SEQ ID NO: 1
  • SEQ ID NO: 9 Nucleotide number of 13 to 6 in SEQ ID NO: 1
  • SEQ ID NO: 10 base number 280 to 300 of SEQ ID NO: 6
  • the antisense oligonucleotide of the present invention is characterized in that nucleotides are connected to each other by a nitrogen-phosphorus bond as shown in the general formula (I).
  • the antisense oligonucleotide represented by such a general formula has a more excellent tumor-suppressing effect than a conventional antisense oligonucleotide having a binding mode such as phosphorothioate, as described in Examples below.
  • the antisense oligonucleotide of the present invention can be synthesized while controlling the nucleotide sequence by successively extending nucleotides according to the following reaction formula.
  • tetrazole is further substituted with 3'-amino group of 3'-amino-5'-dimethyltrityldeoxyribonucleotide in the presence of triethylamine, and this dimethyltrityl Condensation of 3'-amino5'-dimethyltrityldeoxyribonucleoside in the same manner If it returns Repetitive, ethoxy Xia Roh Foss phosphoroamidate on polymer attached by a bond of a fixed arbitrary nucleotide sequence in E ester bond O Rigo nucleotides are obtained. This Is subjected to dedimethyltritylation and deesterification using ammonium to obtain an oligonucleotide having a structure represented by the general formula (I).
  • an oligonucleotide having an arbitrary nucleotide sequence can be automatically obtained by using a commercially available DNA synthesizer and the above reaction reagent.
  • a nucleoside in which the sugar chain part is replaced with 2′-acyl-3′-amino-5′-dimethyltritylribose is used, an RNA-like antisense oligonucleotide can be obtained.
  • the anticancer agent of the present invention comprises at least one selected from the above-mentioned oligonucleotides.
  • an oligonucleotide is used as a mixture of two or more, a higher anticancer effect may be obtained.
  • the anticancer agent of the present invention exhibits an excellent anticancer effect on various cancer cells.
  • the cancer for which the anticancer agent of the present invention is effective is not particularly limited as long as it is a human cancer.
  • the antisense oligonucleotide which is the anticancer agent of the present invention, is expected to be ineffective in some cases because it is an antisense oligonucleotide to the human protein kinase A-RI ⁇ ⁇ gene. You.
  • cancers for which the anticancer agent of the present invention is effective include leukemia, colon cancer, rectal cancer, colon cancer, lung cancer, stomach cancer, liver cancer, kidney cancer, malignant lymphoma, tongue cancer, esophageal cancer, breast cancer, Includes pharyngeal cancer, brain tumor, malignant fibroids, melanoma, cervical cancer, etc.
  • the preferred dosage of the anticancer drug of the present invention varies depending on the disease type, medical condition, age, weight, gender, physical condition, etc., but it is approximately 10 to 200,000 mg once or several times per adult per day. It is appropriate to administer in divided doses.
  • the administration route include intravenous, intraarterial, intraportal, subcutaneous, intradermal, intramuscular, and intralesional injection, and oral administration.
  • the pharmaceutical composition of the present invention comprises the above-mentioned anticancer agent and an optional component in the dosage form.
  • the optional components in the dosage form can be used without any particular limitation as long as they are commonly used in pharmaceutical compositions.
  • oral preparations include bulking agents, binders, flavoring agents, disintegrating agents, lubricants, S-coated agents, sugar coatings, etc.
  • injections include pH regulators, isotonic agents , Stabilizers and the like can be exemplified. It may be formulated together with other drugs known to have anticancer effects.
  • the method of forming these anticancer agents and optional components into dosage forms may be a conventional method. Detailed Description of Preferred Embodiments B Month The present invention will be described more specifically with reference to the following examples.
  • Example 1 Production Example of Antisense Oligonucleotides (1) SEQ ID NOs: 2, 3, 4, 5, and 5 were prepared using the nucleic acid synthesizer ABI384 Synthesizer (manufactured by Applied Biosystems) by the method described above. DNA-type oligonucleotides having the nucleotide sequences shown in 7, 8, and 9 were synthesized. That is,
  • the dimethyltritylated nucleoside having the 3 'terminal base of each sequence fixed to the polymer with an ester bond was treated with a 3% methylene chloride solution of dichlorodic acid for 1.5 minutes to perform a dedimethyltritylation reaction.
  • Phosphitylation was carried out using 0.2 mol of (2-cyanoethoxy)-(N, N-diisopropylamino) clophosphine and 0.2 mol of N, N-diisopropylethylamine in methylene chloride. The reaction was carried out for 10 minutes to obtain cyanoethoxynucleotide.
  • nucleosides are sequentially linked in accordance with each base sequence. Nucleotide removal was performed. The base sequence was previously input to the automatic synthesizer.
  • Example 2 Production Example of Antisense Oligonucleotide (2) A reaction was carried out in the same manner as in Example 1 except that the monomer nucleoside was changed to 2′-acetyl-13′-amino-1,5,1-dimethyltritylribonucleoside, An RNA-type oligonucleotide having the sequence shown in SEQ ID NO: 10 was produced.
  • Example 3 Production Example of Antisense Oligonucleotide (3) Synthesizing a DNA type oligonucleotide having a sequence in which two bases GG at the 5 ′ end of the base sequence shown in SEQ ID NO: 2 were replaced with TT in the same manner as in Example 1. did.
  • Example 4 Anticancer Action on Leukemia Cells (In Vitro) The oligonucleotides produced in Examples 1 to 3 were examined for their growth inhibitory action using HL-60 leukemia cells. That is, cells cultured in RPMI 1640 medium supplemented with 1096 FBS (fetal calf serum) and washed twice with PBS (phosphate buffered saline) were added to RPMI 1640 medium supplemented with 10% FBS.
  • FBS fetal calf serum
  • the thiooligonucleotide of SEQ ID NO: 1 (21-mer) described in JP-A-6-211889, that is, the binding mode of the oligonucleotide of SEQ ID NO: 2 in Example 1 of the present invention was used as a positive control. What was converted from phosphoramidate to phosphorothioether was used. Table 1 shows the results.
  • the oligonucleotide of the present invention has an anticancer effect and that the oligonucleotide of the present invention has an excellent anticancer effect as compared with the conventional oligonucleotide.
  • Oligonucleotide i * 3 ⁇ 4r inhibition degree (uM) Example 1 SEQ ID NO: 202
  • Example 4 for Example 5 colon cancer cells Like the Antitumor effects (in vitro) Example 4 for Example 5 colon cancer cells, the t complete growth inhibition minimum concentration viewed antiproliferative activity using colon cancer-derived cell LS 1 7 4 T in Table 2 Show. This indicates that the oligonucleotide of the present invention also has the same effect on colon cancer as leukemia.
  • Colon cancer-derived cells LS174T were used to transplant them into nude mice (male, 5 mice per group), and the present invention was used to examine the proliferation.
  • the oligonucleotide should be mixed and emulsified with 49.5% peanut oil, 49.5% saline and 196 Tween 80 so that the final concentration of the oligonucleotide would be 1 Omg / ml.
  • the sample mixed with the vehicle was subcutaneously administered to a 0.0 lm 1 tumor and the left back skin, and the size of the tumor was measured after the administration.
  • the average volume of tumor in the oligonucleotide-administered group was subtracted from the average volume of tumor in the non-administered group, and this value was divided by the average volume of tumor in the non-administered group, multiplied by 100.
  • oligonucleotide of the present invention an oligonucleotide having the sequence shown in SEQ ID NO: 2 was used, and as a control, the phosphorothioate-type oligonucleotide shown in Example 1 was used.
  • the growth inhibitory rate of the oligonucleotide of the present invention was 71%, whereas the oligonucleotide of the control product was 35%. This indicates that the oligonucleotide of the present invention has an excellent anticancer effect even in vivo. In addition, no undesired toxicity was observed even after administration of the oligonucleotide, indicating that the therapeutic index indicated by the safety and the effective concentration for toxicity was high.
  • Example 7 Effect of Combination of Antisense Oligonucleotides of Diplomacy Similar to Example 4, the oligonucleotide of the present invention having the sequence shown in SEQ ID NO: 2 and the oligonucleotide of the present invention having the sequence shown in SEQ ID NO: 3, etc.
  • the molar mixture was tested for its anticancer effect on HL-60.
  • the minimum cytostatic concentration was 0.4 ⁇ M (a mixture of 0.2 M of the oligonucleotide of the present invention of SEQ ID NO: 2 and 0.2% of the oligonucleotide of the present invention of SEQ ID NO: 3), which was additive. It can be seen that the effect is more than the effect.
  • INDUSTRIAL APPLICABILITY The antisense oligonucleotide for the protein kinase A gene of the present invention has a high anticancer effect, and thus is very useful as an anticancer agent and a medical composition for treating cancer.

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Abstract

Cette invention se rapporte à un oligonucléotide anti-sens contre la protéine-kinase A-RIα dont l'effet cancérostatique est amélioré et qui contient comme agent cancérostatique un oligonucléotide ayant la structure représentée par la formule générale (I) et possédant une séquence de base qui est essentiellement complémentaire d'une partie de la séquence de base du brin codant des gènes de protéine-kinase A-RIα humains représentée par le numéro d'identification de séquence: 1, ou une séquence de base qui est essentiellement complémentaire d'une partie de la séquence de base du brin non codant desdits gènes. Dans la formule (I), n représente un nombre entier; R représente hydrogène ou hydroxy; et B représente une base d'acide nucléique.
PCT/JP1995/002452 1994-12-02 1995-12-01 Oligonucleotide anti-sens et agent cancerostatique contenant cet oligonucleotide WO1996016976A1 (fr)

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JP6324006A JPH1135595A (ja) 1994-12-02 1994-12-02 アンチセンスオリゴヌクレオチド及びそれを用いた制癌剤
JP6/324006 1994-12-02

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997011171A1 (fr) * 1995-09-22 1997-03-27 Hybridon, Inc. Oligonucleotides modifiees specifiques de la proteine kinase a et leurs modes d'utilisation
WO1998040479A1 (fr) * 1997-03-12 1998-09-17 Hybridon, Inc. Oligonucleotides modifies specifiques de la proteine kinase a et methodes d'utilisation
WO2001040285A1 (fr) * 1999-11-30 2001-06-07 Bioroad Gene Development Ltd. Shanghai Nouveau polypeptide, proteine kinase 38, et polynucleotide codant pour ce polypeptide
WO2002012299A1 (fr) * 2000-07-07 2002-02-14 Biowindow Gene Development Inc. Shanghai Nouveau polypeptide, proteine kinase humaine 27.17, et polynucleotide codant ce polypeptide
US6624293B1 (en) 1995-08-17 2003-09-23 Hybridon, Inc. Modified protein kinase A-specific oligonucleotides and methods of their use
US7074768B2 (en) 1995-08-17 2006-07-11 Idera Pharmaceuticals, Inc. Modified protein kinase A-specific oligonucleotides and methods of their use
US7528117B2 (en) * 2002-12-05 2009-05-05 The Research Foundation Of State University Of New York High efficacy antisense RIαPKA poly-DNP oligoribonucleotides

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993013740A2 (fr) * 1991-12-31 1993-07-22 Worcester Foundation For Experimental Biology Oligonucleotides antiparasitaires efficaces contre la malaria resistant aux medicaments

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993013740A2 (fr) * 1991-12-31 1993-07-22 Worcester Foundation For Experimental Biology Oligonucleotides antiparasitaires efficaces contre la malaria resistant aux medicaments

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6624293B1 (en) 1995-08-17 2003-09-23 Hybridon, Inc. Modified protein kinase A-specific oligonucleotides and methods of their use
US7074768B2 (en) 1995-08-17 2006-07-11 Idera Pharmaceuticals, Inc. Modified protein kinase A-specific oligonucleotides and methods of their use
WO1997011171A1 (fr) * 1995-09-22 1997-03-27 Hybridon, Inc. Oligonucleotides modifiees specifiques de la proteine kinase a et leurs modes d'utilisation
WO1998040479A1 (fr) * 1997-03-12 1998-09-17 Hybridon, Inc. Oligonucleotides modifies specifiques de la proteine kinase a et methodes d'utilisation
WO2001040285A1 (fr) * 1999-11-30 2001-06-07 Bioroad Gene Development Ltd. Shanghai Nouveau polypeptide, proteine kinase 38, et polynucleotide codant pour ce polypeptide
WO2002012299A1 (fr) * 2000-07-07 2002-02-14 Biowindow Gene Development Inc. Shanghai Nouveau polypeptide, proteine kinase humaine 27.17, et polynucleotide codant ce polypeptide
US7528117B2 (en) * 2002-12-05 2009-05-05 The Research Foundation Of State University Of New York High efficacy antisense RIαPKA poly-DNP oligoribonucleotides

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