WO1990015813A1 - Alpha anomer oligonucleotide compounds which inhibit retrovirus replication - Google Patents
Alpha anomer oligonucleotide compounds which inhibit retrovirus replication Download PDFInfo
- Publication number
- WO1990015813A1 WO1990015813A1 PCT/FR1990/000412 FR9000412W WO9015813A1 WO 1990015813 A1 WO1990015813 A1 WO 1990015813A1 FR 9000412 W FR9000412 W FR 9000412W WO 9015813 A1 WO9015813 A1 WO 9015813A1
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- WO
- WIPO (PCT)
- Prior art keywords
- sequence
- alpha
- group
- oligonucleotide
- compounds
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- 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
-
- 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
- C07H21/04—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with deoxyribosyl as saccharide radical
-
- 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
- C12N15/1131—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 viruses
- C12N15/1132—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 viruses against retroviridae, e.g. HIV
-
- 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
- C12N2310/33—Chemical structure of the base
- C12N2310/337—Chemical structure of the base in alpha-anomeric form
Definitions
- the present invention relates to chemical compounds consisting of an oligonucleotide or an oligodeoxynucleotide comprising a chain of nucleotides having the non-natural anomeric configuration alpha as opposed to the natural anomeric configuration beta.
- the present invention relates to such oligonucleotide compounds useful for inhibiting the replication of a retrovirus and, in particular, an oligonucleotide compound useful for inhibiting the replication of the HIV virus.
- the compounds according to the invention consist of an oligoribonucleotide or oligodeoxyribonucleotide sequence of unnatural anomaly alpha, said sequence being complementary to a sequence included in the sequence called TBS or PBS (tRNA binding site or primer binding site) consisting of the binding site of the viral RNA replication tRNA primer or in a viral RNA sequence upstream of the TBS sequence.
- TBS tRNA binding site or primer binding site
- alpha oligonucleotide compounds according to the invention can optionally be linked coschreibly to an effector agent, such as an intercalating agent, in reactive or photoactivable chemical radical.
- an effector agent such as an intercalating agent, in reactive or photoactivable chemical radical.
- the radicals B can be identical or different and each represent a base of a nucleic acid possibly modified and attached to the glycosidic cycle according to an unnatural alpha anomeric configuration.
- radicals B being complementary one to one of the bases of the target oligonucleotide sequence included in the TBS sequence or a sequence upstream of the proviral RNA;
- the radicals X may be the same or different and each represents an oxoanion Q ⁇ , a thioanion S ⁇ , an alkyl group, an alkoxy group, aryloxy, an aminoalkyl group, an aminoalkoxy group, a thioalkyl group;
- R and R ' which may be the same or different, each represent a hydrogen atom or a group -Y-Z;
- Y represents a straight or branched alkylene radical -alk- or a radical chosen from
- E can have the same meanings as X;
- J represents a hydrogen atom or a hydroxy group
- Z is a radical corresponding to an effector
- n is an integer including O
- L represents an oxygen atom, a sulfur atom or a group
- formula I represents a sequence of nucieotides which may be identical or different, n simply indicating the number of nucieotides included in the molecule; n is preferably a number between 1 and 30, and more preferably between 1 and 20 and depends on the size of the target sequence of the RNA of the retrovirus. In general, for example, the TBS sequences have about twenty nucieotides.
- effector radicals correspond to effector agents which are compounds known in the techniques relating to nucleic acids. These are, for example, compounds capable of "intercalating" in the structure of DNAs or RNAs.
- intercalating agents are especially constituted by polycyclic compounds having a plane configuration such as acridine, furocoumarin, daunomycin, 1,10-phenanthroline, phenanthridinium, prophyrins, dipyrido derivatives (1,2 -a: 3 ', 2'-d) imidazole, ellipticine or ieliipticinium and their derivatives.
- effector agents can also be reactive chemical radicals such as chemical cleavage radicals, that is to say that these radicals can directly or indirectly react to split a chain of nucleotides.
- these reactive chemical radicals will be activatable, for example chemically or photochemically.
- the activatable cleavage reactive groups are, for example, derivatives of compounds such as:
- the radical B consists of a base of a nucleic acid linked to the sugar part of the nucleotide by an alpha anomeric configuration. It can be thymine, adenine, cytosine, guanine or uracil. However, it is also possible to use modified nucleic acid bases, in particular halogenated or azidic, for example the
- 5-bromo-uracil or 8-azidoadenine or amino derivatives such as 2-amino-adenine and its substituted derivatives, for example on the N by an aminoalkylene group or by an azidophenylalkyiene group; or guanine substituted on O ⁇ , for example by a ( ⁇ -alkylene) -9-acridine group or 8- ( ⁇ -aminoalkyl) -ammo-adenine and its derivatives substituted on NH 2 in u) by a group acridine.
- the usual bases are therefore considered, as well as the possibility of introducing modified bases.
- Des. "effector" bases capable of covalently binding to a complementary beta strand, may be introduced.
- the functionalization of C or T by an aziridine group in position 4 leads to the formation of covending cross-links CH 2 -CH 2 between the two complementary strands on G and A respectively.
- the radical B is chosen from thymine, adenine, cytosine, guanine, 4-azido-cytosine or 4-az ⁇ do-thymine and 8-azido-adenine, uracil, 5 bromo-uracil.
- the radical X although it preferably represents an oxoanion, can have other meanings; when the radical X represents an alkyl group, it is preferably a C 1 to C 7 lower alkyl group and, for example, the ethyl, methyl or propyl groups; when the radical X represents an alkoxy group, it is preferably a C 1 to C 7 lower alkoxy group, for example the methoxy or ethoxy group; when X represents an amino-alkyl or amino-alkoxy group; it may be a mono-substituted, disubstituted amino-alkyl group or else an amino radical in the form of a quaternary ammonium salt.
- the substituents are preferably lower alkyl radicals as defined above; as for the alkyl or alkoxy chain connecting the amino radical to the phosphorus, it is preferably a straight branched chain comprising from 1 to 10 carbon atoms.
- the alkyl or alkoxy radical is substituted by a nitrogen heterocycle, it is in particular a saturated 5-6-membered ring comprising a nitrogen atom which may be quaternary.
- the radical X is a thioalkyl radical, it is preferably a lower thioalkyl radical, that is to say which contains between 1 and 7 carbon atoms.
- the radical -alk- is preferably a straight or branched alkylene radical having from 1 to 10 carbon atoms.
- the effector can therefore be introduced via a chain
- the preceding compounds are also concerned in the form of a salt with bases or acids, and the compounds in racemic form, or in the form of purified or mixed optical R or S isomers.
- the preceding compounds are also concerned in the D or L series.
- the subject of the present invention is also anti-sweat pharmaceutical compositions containing, as active substance, said compounds, and in particular compositions useful for the treatment of viral affections of RNA viruses, such as the HIV1 AIDS virus.
- the subject of the present invention is the use of the compounds according to the invention for the preparation of antiviral pharmaceutical compositions in particular useful for the treatment of AIDS.
- the application of the alpha oligonucleotide compounds according to the present invention consists in inhibiting the replication of retroviruses and in particular of the human immunodeficiency virus HIV1 from AIDS.
- LAV iymphadenopathies
- LAV HTLV III virus
- ARV AIDS - related virus
- DNA polymerase - dependent RNA also called reverse transcriptase or more commonly reverse transcriptase.
- This enzyme copies into so-called complementary single-strand DNA (cDNA), viral RNA. This requires that it find an oligonucleotide primer paired at the 3 'end of the RNA template to be copied.
- Reverse transcriptase is both necessary to establish the provirai state, to start the replication of the virus, and to possibly transform the cell.
- the primer is a tRNA of cell origin present inside virions.
- reverse transcriptase RT
- the 3 'tRNA of lysine serves as the start of DNA which will be synthesized.
- the synthesized strand is guided by the primer groove.
- the DNA strand thus synthesized is then in the form of a single strand, following RNase activity linked to RT and a complementary DNA strand is synthesized via polymerase DNA activity dependent on RT.
- the structure of a retrovirus before and after its integration into the DNA of a host cell can be schematized as follows: a) Integration of the retrovirus into the DNA of the host cell, viral RNA
- RNA of a retrovirus is a single stranded RNA in which the coding regions are flanked by sequences essential for viral replication and expression. These sequences are, from the 5 'to 3' end:
- tRNA binding site This is the site where the 3 'tRNA binds (which will serve as a primer during replication).
- the complementary and antiparallel links will cover around 20 bps,
- - coding region it is located in the center, it contains very few genes. Those are :
- glyco for "group specifies antigen”
- gene of the group antigen which codes for a polyprotein which, cut out, gives the proteins of the nuciéoid.
- these internal proteins one of them carries the group's antigenicity
- polymerase for "poiymerase” which codes for reverse transcriptase
- env for "envelope” which codes for envelope giycoproteins.
- env for "envelope”
- coding region can also be found a gene coding for a viral protein (or a segment of protein) specific for the retrovirus (For example, in oncogenic retroviruses, there is an onc gene. This is not the case for the virus of AIDS which is not an oncogenic retrovirus, it does not cancerize the cells but destroys them).
- the transcribed double stranded DNA molecule is longer than the corresponding genomic DNA. Indeed, there is addition at the 2 ends of 2 sequences:
- LTR long terminal repeat
- the double stranded linear DNA becomes circular closed, then it is again opened to be integrated into the DNA of the host cell.
- the integrated viral DNA is called "provirus".
- the dinuciéotides (TT, AA) located at the ends of the transcribed DNA (and being part of U 3 or U 5 ) are eliminated.
- direct repeat a direct repeated sequence
- All CDs are 4 to 6 bps long. Their sequences are different. For the same provirus, moreover, there are different DRs in the DNA of a host cell. The site of integration of the virus is therefore not specific, the virus can be integrated into the genome of the host in several different places.
- antisense oligonucleotides that is to say segments of DNA complementary to a portion of the messenger RNA of the virus which directly codes for the proteins to be synthesized. by the ribosome.
- alpha oligonucleotides form heteroduplexes with their beta complementary oligonucleotides and that these are not substrates for the enzyme RNase H, it could be thought that the inhibition of the expression of proteins by the alpha oligonucleotide perhaps could be accomplished by preventing the ribosome from translating mRNA into viral protein.
- the approach according to the present invention aimed at using oligonucleotides complementary to an initial sequence of the viral RNA and in particular of the initial lvsin tRNA binding site on provirai RNA, has been shown to be effective.
- FIG. 1 represents the inhibition of the viral production of MT4 cell by the 5 'alpha d oligonucleotide (ACCGCGGGCTCTGTCCCTG) 3' (oligo alpha "PBS") by assaying the activity (cpm) of reverse transcriptase.
- EXAMPLE 1 Cytotoxicity of alpha oligonucleotides
- oligonucleotide whatever type of oligonucleotide is used, these end up more or less rapidly being degraded by cellular enzymes. It is shown below that the oligonucleotides alpha and their catabolites nucleosides al pha and nucleotide alpha do not exhibit cytotoxicity.
- the oligonucleotide alpha-d (CCTCTCGTTCTTTAC) oligo alpha Tat (complementary) of the Tat sequence directed, a priori, against any site of the genome of the MT-4 cells, has a CD 50 greater than 250 ⁇ g / ml.
- alpha oligothymidylates alpha- (dT) n (2 ⁇ n 12 12) have been found to be non-cytotoxic to the same cell line.
- al pha nucleosides and alpha nucleotides which can result from the hydrolysis of oligonucleotides are also devoid of cytotoxicity against various cell lines (Hela, Vero, primary rabbit kidney cells. MT-4).
- the evaluation is based on the study of the cytopathogenic effect of the HIV1 virus on the MT4 cell line, after infection with the HIV1 virus, the formation of syncitia is observed 4 to 6 days after infection, followed by production of viral particles, then by cell death.
- T4 lymphocytes essential for immune defense are the first cause of the immune deficiency characteristic of HIV infection.
- This virus kills cells by multiplying in them; when it escapes, it damages the cell membrane.
- HIV may also kill T4 cells indirectly, by the gp l protein 20 present on the membrane of infected cells.
- T4 lymphocytes carry a surface molecule, the CD4 receptor, to which the GP120 protein binds; healthy T4 cells attach to the protein and fuse with the infected cell.
- the cell mass that forms is a "syncytiuni", unable to survive, and all the healthy cells that compose it die with the infected cell. HIV can also trigger normal immune responses against infected lymphocytes.
- defense cytotoxic cells destroy an infected cell carrying viral proteins on its surface.
- the protein gp120 sometimes circulates freely in solution in the blood of infected subjects; it binds to the CD4 receptor of healthy cells, simulating an infection and triggering a reaction of destruction of uninfected cells.
- Syncytia are structures formed by several nuclei surrounded by a single cell membrane; These are signs of HIV infection in cell cultures; Syncytia are formed when infected cells that synthesize and transport the gp120 molecule on their surface merge with healthy cells carrying the CD4 molecule. b) Compound tested
- the MT4 cells on day 2 after the last passage are pre-incubated for 1 hour at 37 ° C. with the successive dilutions of the compound at the rate of 3.10 cells per 100 ⁇ l of compound (in 96-well micropaque).
- the infection is carried out in microwells by adding 100 ⁇ l of a 10 - 4 dilution of the HIV1 virus (the dilution of the virus was determined to induce the formation of syncitia in 4 days).
- the infected MT4 cells are washed 5 times before being cultured at a concentration of 3.10 cells per ml, in a 24-well microplate, in the presence of the various dilutions chosen.
- the cells are diluted 3 or 4 times and adjusted to the concentration of 3.10 cells / ml with RPM 1 medium 10% FCS 1% PSN 1% Gluta always in the presence of oligo alpha PBS.
- FIG. 1 RT reverse transcriptase
- FIG. 1 RT Monitoring of viral production of MT4 cells is carried out by assaying the activity of reverse transcriptase (FIG. 1 RT) in the culture every 3 or 4 days. Briefly, the enzymatic activity is tested using a synthetic primer and a H 3 radiolabelled substrate "in vitro". The quantity of radiolabelled material precipitated, expressed in counts per minute, is proportional to the activity of the reverse transcriptase itself proportional to the quantity of virus produced by the infected MT4 cells.
- PBS used, the viral production remains lower than that obtained in the presence of the HIV1 virus, with a peak of delayed maximum viral production.
- the oligonucleotide "alpha Tat” corresponds to the oligonucleotide alpha d 5 GTAAAAGTCTTAACCCAC 3 ' . It is complementary to the sequence of the Tat gene of the AIDS virus.
- the oligo nucleotide "alpha random” corresponds to any olna nucleotide alpna d 5 ' ACTGACTGACTGACTGAC 3' .
- the oligonucleotide "alpha PBS” shows an inhibition of viral production for concentrations of 100 ⁇ g / ml and 50 ⁇ g / mi.
- oligonucleotide "alpha PBS” has an antiviral effect on the HIV1 virus at concentrations of 100 ⁇ g / ml and 50 ⁇ g / ML, while the oligonucleotide "alpha Tat" and the oligonucleotide " alpha Random "have no antiviral effect.
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR89/07782 | 1989-06-13 | ||
FR8907782A FR2648045B1 (en) | 1989-06-13 | 1989-06-13 | ALPHA ANOMERIC OLIGONUCLEOTIDE COMPOUNDS INHIBITING REPLICATION OF RETROVIRUSES |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1990015813A1 true WO1990015813A1 (en) | 1990-12-27 |
Family
ID=9382646
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/FR1990/000412 WO1990015813A1 (en) | 1989-06-13 | 1990-06-12 | Alpha anomer oligonucleotide compounds which inhibit retrovirus replication |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP0477248A1 (en) |
JP (1) | JPH04506074A (en) |
FR (1) | FR2648045B1 (en) |
WO (1) | WO1990015813A1 (en) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0527916A1 (en) * | 1990-05-11 | 1993-02-24 | Isis Pharmaceuticals, Inc. | Antisense inhibitors of the human immunodeficiency virus |
FR2717081A1 (en) * | 1994-03-14 | 1995-09-15 | Centre Nat Rech Scient | Retropeptides, antibodies against them, and their uses for vaccination and in vitro diagnosis. |
EP1016715A1 (en) * | 1992-09-29 | 2000-07-05 | Isis Pharmaceuticals, Inc. | Oligonucleotides having a conserved G4 core sequence |
US6776986B1 (en) | 1996-06-06 | 2004-08-17 | Novartis Ag | Inhibition of HIV-1 replication by antisense RNA expression |
WO2008037924A2 (en) | 2006-09-28 | 2008-04-03 | Biomerieux | Novel labelled oligonucleotide |
US8663923B2 (en) | 2008-07-04 | 2014-03-04 | Biomerieux | Detection probe |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1988004301A1 (en) * | 1986-12-02 | 1988-06-16 | Centre National De La Recherche Scientifique (Cnrs | alpha OLIGONUCLEOTIDES |
WO1988008001A1 (en) * | 1987-04-16 | 1988-10-20 | Aktiebolaget Astra | Nucleosides and nucleoside analogues, pharmaceutical composition and processes for the preparation of the compounds |
WO1989003217A1 (en) * | 1987-10-14 | 1989-04-20 | Centre National De La Recherche Scientifique (Cnrs | ANTIVIRAL APPLICATION OF alpha OLIGONUCLEOTIDES |
-
1989
- 1989-06-13 FR FR8907782A patent/FR2648045B1/en not_active Expired - Fee Related
-
1990
- 1990-06-12 EP EP90909462A patent/EP0477248A1/en not_active Ceased
- 1990-06-12 WO PCT/FR1990/000412 patent/WO1990015813A1/en not_active Application Discontinuation
- 1990-06-12 JP JP2508923A patent/JPH04506074A/en active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1988004301A1 (en) * | 1986-12-02 | 1988-06-16 | Centre National De La Recherche Scientifique (Cnrs | alpha OLIGONUCLEOTIDES |
WO1988008001A1 (en) * | 1987-04-16 | 1988-10-20 | Aktiebolaget Astra | Nucleosides and nucleoside analogues, pharmaceutical composition and processes for the preparation of the compounds |
WO1989003217A1 (en) * | 1987-10-14 | 1989-04-20 | Centre National De La Recherche Scientifique (Cnrs | ANTIVIRAL APPLICATION OF alpha OLIGONUCLEOTIDES |
Non-Patent Citations (1)
Title |
---|
Nucleosides & Nucleotides, Volume 8, No 5&6, 1989, Marcel Dekker, Inc., R. PAUWELS et al.: "Alpha-Oligodeoxynucleotides as Inhibitors of HIV Reserve Transcriptase", pages 995-1000 * |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0527916A1 (en) * | 1990-05-11 | 1993-02-24 | Isis Pharmaceuticals, Inc. | Antisense inhibitors of the human immunodeficiency virus |
EP0527916A4 (en) * | 1990-05-11 | 1994-04-06 | Isis Pharmaceuticals, Inc. | |
EP1016715A1 (en) * | 1992-09-29 | 2000-07-05 | Isis Pharmaceuticals, Inc. | Oligonucleotides having a conserved G4 core sequence |
FR2717081A1 (en) * | 1994-03-14 | 1995-09-15 | Centre Nat Rech Scient | Retropeptides, antibodies against them, and their uses for vaccination and in vitro diagnosis. |
WO1995024916A1 (en) * | 1994-03-14 | 1995-09-21 | Centre National De La Recherche Scientifique | Retropeptides, antibodies thereto, and uses thereof for vaccination and in vitro diagnosis |
US6776986B1 (en) | 1996-06-06 | 2004-08-17 | Novartis Ag | Inhibition of HIV-1 replication by antisense RNA expression |
WO2008037924A2 (en) | 2006-09-28 | 2008-04-03 | Biomerieux | Novel labelled oligonucleotide |
FR2906532A1 (en) * | 2006-09-28 | 2008-04-04 | Biomerieux Sa | NEW OLIGONUCLEOTIDE BRAND |
WO2008037924A3 (en) * | 2006-09-28 | 2008-07-31 | Biomerieux Sa | Novel labelled oligonucleotide |
US8158345B2 (en) | 2006-09-28 | 2012-04-17 | Biomerieux | Labeled oligonucleotide |
US8663923B2 (en) | 2008-07-04 | 2014-03-04 | Biomerieux | Detection probe |
Also Published As
Publication number | Publication date |
---|---|
FR2648045B1 (en) | 1991-09-27 |
JPH04506074A (en) | 1992-10-22 |
FR2648045A1 (en) | 1990-12-14 |
EP0477248A1 (en) | 1992-04-01 |
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