Oligonucleotides, the pharmaceutical composition

 

(57) Abstract:

The invention relates to oligonucleotides and their derivatives to suppress the expression of isoprenylation, pharmaceutical compositions containing such compounds and to the use of such compositions of oligonucleotides for the treatment or therapy of the human or animal diseases caused by abnormal and/or unregulated proliferation. Oligonucleotides have the formula (I): P - O-R (I), where P is absent or is a sequence of one or more bases selected from A (adenine), T(thymine), C (cytosine) and G (guanine); is a sequence selected from: SEQIDN1: AGAAGCCATG AT; SEQIDN2: GGACGTGACT GT; SEQIDN3: AAGGAGTAGC AG; SEQIDN4: CAGGCAGTAG CA; SEQIDN5: CCCGTCGTCC AT; SEQIDN6: CTGTCCCTGT AC; SEQIDN7: ACTTCTCTCT CC; SEQIDN8: ACTTGGTCCT AA; SEQIDN9: GCCATCATTC TG; SEQIDN10: GATCTGGACC AC; SEQIDN11: CTCAATAGCA TC; SEQIDN12: GTTTTTGGGG TG; SEQIDN13: TCTCACATCC TC; SEQIDN14: TTGTAAGAAC TG; SEQIDN15: GAAGTGCTTC TC; SEQIDN16: GCCTCTTTC AG; SEQIDN17: GGCATCTGTC AG; SEQIDN18: CGGCTGGCAT CC; SEQIDN19: GAACTGACAC AC; SEQIDN20: ACGATCACAT CA; SEQIDN21: ATCAACATGC AG; SEQIDN22: CTGCATATCG AC; SEQIDN23: CAGTGCACCA GC; SEQIDN24: CTGCAGCCTC GG; SEQIDN25: ACTCTGGA CC; SEQIDN26: CAAGAATCCT CG; SEQIDN27: ACATCTGCTC TG; SEQIDN28: TCTGTACTCG TC; SEQIDN29: CTACAGTACA GC; SEQIDN30: CCCGTCGTCC ATAGG; SEQIDN31: CCCGTCGTCC ATAGGGGA; SEQIDN32: CCCGTCGTCC ATAGGGGAC GC; SEQIDN33: GGACGTGACT GTTTC; SEQIDN34: GGACGTGACT GTTTCCAC; SEQIDN35: GGACGTGACT GTTTCCACTG; SEQIDN36: GGACGTGACT GTTTCCACTG AGTC, R is either missing or predstavlja, possessing antiproliferative action, containing as active ingredient an effective amount of at least one of the oligonucleotide of formula (I) in a mixture with a pharmaceutically acceptable diluent and/or carrier suitable for the chosen route of administration. 2 C. and 12 C.p. f-crystals, 9 PL.

The invention relates to oligonucleotides and their derivatives, which inhibit the expression of isoprenylcysteine, therapeutic compositions containing such compounds, and the use of such compositions of oligonucleotides for the treatment or therapy of the human or animal diseases caused by abnormal and/or deregulated cell proliferation.

Any living organism, whether unicellular or multicellular, characterized by the ability to reproduce the phenomenon, requiring replication of the material of heredity (DNA etc) and the same distribution of replicated DNA between the two "daughter" cells. There are a large number of very different molecules with mitogenic activity, which are "specific to cells". "Signal" molecules or growth factors are the types of polypeptides, which in very low quantities and after vzaimodeistvie growth effect on the cell cycle does not directly and by interacting with a series of transmembrane receptors located on the plasma membrane nesenevich cells, and their activation. This triggers a chain reaction in the cell, which leads to mitosis. Activated intracellular events may vary from one cell type to another for the same receptors.

One of the first stages binding growth factor with its receptor consists in the activation of protein kinase and phosphorylation of proteins. One of the proteins that form the cell signal transduction, is a protein ras protein in 21-Dalton, modified by using a mechanism prenisolone. Prenisolone is a post-translational modification, which involves the covalent binding of isoprenaline groups with cysteine numerous proteins. Thus, isoprenaline can be transfer farnesenes group or geranylgeranyl group to Milenium proteins. This modification allows some proteins to contact the place of action on the membrane. Thus, one result of the suppression of this prenisolone is to prevent the transduction of extracellular signals to the nucleus and, consequently, cell proliferation.

s: farnesyltransferase, geranylgeranyltransferase type 1 and geranylgeranyltransferase type 2. These enzymes recognize a consensus sequence located at the C-ends of the proteins.

One of the consequences of blocking the synthesis of these enzymes is the blockade of the major pathways of signal transmission, which leads to cell proliferation.

Most classical active ingredient interacts with the protein, the product of translation of the genetic information and inhibit their function. This invention is directed to modern therapeutic approach: antisense strategy. This approach involves the selective modulation of gene expression by selective connection of the nucleotide chain (oligonucleotides) with them complementary sequence on a matrix or pragmatichnoj RNA or DNA and, therefore, inhibited the synthesis of the corresponding protein. Used molecules interact directly with the system of genetic information.

Oligonucleotides complementary to the transcription products, called "antimuslim" oligonucleotides. Oligonucleotides having the same sequence as the products of transcription are known as "Smyslovye gene product by removing the corresponding messenger RNA using the hydrolysis of RNA Asai H. It soon became clear that the mechanism of action of these antisense oligonucleotides is not so simple. These oligonucleotides can interact with different number of cellular targets, which are not nucleic acids. These oligonucleotides can interact with the genome with the formation of structures with triple helix and suppression of formation of products of transcription. Oligonucleotides can interact with intranetname compounds pragmatichnoj RNA, interfering thus the correct splicing of the transcription product. Oligonucleotides could gibridizatsiya with mRNA in the cytoplasm by the formation of duplex RNA-DNA, which is quickly destroyed by the enzyme RNA Asai H or preventing the movement of the ribosomal complex on the mRNA, blocking, so the broadcast. Oligonucleotides, particularly modified oligonucleotides, can interact with a number of cellular components such as proteins. These interactions could be specific for the sequence (e.g., transcription factors) or could be non-specific for the sequence (e.g., growth factors). Thus, oligonucleotides (PEFC ID N 1-36) may result in stopping proliferation by any one or combination of valenzuala to block the synthesis of enzymes, as specified above. This suggests their use as antiproliferative funds in cardiovascular diseases, Oncology, dermatology, some viral infections and any pathological conditions associated with cell proliferation.

When antisense methodology can be used antisense oligonucleotides or antisense RNA. The methodology antimyeloma oligonucleotide differs from the methodology antimyeloma RNA. When the last segment of DNA of a gene is embedded in the vector DNA in the opposite orientation normal meaning and, thus, during the transcription of the specified vector of one of the chains of DNA is replicated in RNA. Inserting a gene fragment with reverse sequence results in the synthesis of in situ RNA, which is complementary to the normal mRNA synthesized by the cell. This RNA, called antisense RNA may gibridizatsiya expressed with normal mRNA and, thus, to suppress the transmission mesiniaga protein. This method was used Prendergast et al. (Cell Growth and differenciation 4,707-713, September 93) to evaluate the role farnesyltransferase, cDNA for - subunit of this farnesyltransferase has cloned and purified; he is>Method with antisense RNA is particularly useful as a mechanistic tool to investigate the role of protein in the cell, and in the end, as a therapeutic agent using sophisticated subtle techniques of gene therapy, whereas antisense oligonucleotides more attractive as pharmaceuticals and are considered by regulatory authorities (regulatory sources) as classical chemical substances. In addition, oligonucleotides can be easily synthesized in large volume using classical chemistry, whereas molecule antisense RNA receive in a biological system and there are numerous obstacles to its production in an industrial scale.

Method of dosing farnesyltransferase was studied in EP 456180: more specifically, using the specified method can be measured activity of potential inhibitors farnesyltransferase. But in any case this method does not allow one to determine the structure of the new potential inhibitor farnesyltransferase, and this patent also does not describe any molecule, related to this invention.

The invention is an oligonucleotide (odinic isoprenylation and preferably, for the subunits and/or isoprenylation. The oligonucleotide may include from 2 to 50, preferably from 8 to 35 units. More preferably, the oligonucleotide contains from 10 to 25 units.

The oligonucleotides of this invention can be synthesized by any known method of chemical synthesis of oligonucleotides. The oligonucleotides is most appropriate to get using any commercially available automatic nucleic acid synthesizer. One of the methods of synthesis of oligonucleotides is betacarotene method described by S. L. Beaucage and al (Tet Let. 22 (1981) 1859-1862).

The invention is also derivatives of such oligonucleotides, i.e., oligonucleotides, in which the skeleton has been modified along the length of the oligonucleotide or in one of the positions 5' or 3', or both. In fact, the oligonucleotides are sensitive to nucleases enzymes that hydrolyzing them to nucleotides, oligonucleotides become resistant to nucleases by modifying, for example, the chemical nature of the sugar or phosphate - sugar mezhnukleotidnyh relations: thus fosfomifira chain may be replaced by, for example, phosphorothioates, phosphorodithioates chain. Can be done other types of modifications along the entire length of the oligonucleotide, or 5' and/or 3' ends of the oligonucleotides, to make the oligonucleotide more stable in the biological environment. As well as, phosphate bonds between the nucleotides could be replaced amide bonds (peptide nucleic acid). Moreover, the transmembrane transfer of oligonucleotides can be accelerated by turning the latter in a more hydrophobic: this can be achieved, for example, by attaching hydrophobic substituents, such as cholesterol or aromatic groups, or a polymer. Partially or over the entire length of the oligonucleotide can include modified bases. Also partially or over the entire length of the oligonucleotide could be included conformationally modified nucleotides (e.g., oligonucleotide - -anomeric conformation), resistant to nucleases or with properties of high hybridisable or intracellular penetration. Thus, the term "derivative" includes a nucleotide, a modified one of the methods described above, or by any other means well known to the specialist.

Preferred oligonucleotides of this invention are oligonucleotides with sequences or sense oligonucleotides, according to this invention.

The invention, furthermore, represents an oligonucleotide containing at least part of one of the sequences selected from TH ID N 1 TH ID No. 36.

The invention, in addition, provides therapeutic compositions comprising as active ingredient at least one antisense oligonucleotide according to this invention in a mixture with a pharmaceutically acceptable diluent and/or carrier suitable for the chosen route of administration. The composition can be applied by local, systemic or local treatment, it may take the form of a liquid or injection, liposomes, dosage form with prolonged isolation, gel, ointment for local application or any other acceptable form for the chosen method of administration.

Finally, the invention is the use of the compositions of this invention in a method of treatment of a human or an animal, which is abnormal and/or deregulated cell proliferation.

The following examples illustrate the invention.

Example 1. Effect of antisense oligonucleotide on the proliferation of smooth muscle cells of rats.

Smooth muscle cells of the aorta cu is outstay medium DMEM, 10% fetal calf serum (FCS), 2 mm glutamine, 50 U/ml penicillin and 50 µg/ml streptomycin. Used smooth muscle cells between 3 m and 7 m passengers in 24 cell boards.

After 3 days of culturing cells isolated serum for 72 hours. Cells are then stimulated (or not) of 1% serum or 5 ng/ml bFGF (basic fibroblast growth factor) and processed simultaneously in the presence or in the absence of the products of this invention at a concentration of 10-5M within 24 hours. Four hours before the end of the incubation, the cells were labelled with thymidine containing tritium (1 µs/ml). The inclusion stopped by the addition of 5% THU 10 minutes, then the cells were adjusted to 500 µl of 0.5 N. NaOH. Samples of 400 µl were collected and placed in vials for determination of scintillation containing 400 µl of 0.5 N. HCl and 10 ml.

The activity of the oligonucleotides is determined by measuring cell proliferation, expressed in percentage. The results obtained are shown in table. 1.

Example 2. The dependence of the response on the dose. Effect of antisense sequences on the proliferation of smooth muscles of rats.

The plan of the experiment was identical to that described in example 1. Cell processing is SUP>M (see tab. 2).

Example 3. Size influence on the biological activity in vitro antisense oligonucleotides.

The experiment was identical to that described in example 1. Cells were treated with compounds of this invention (see tab. 3).

Example 4. Study of in vitro antiproliferative action of antisense oligonucleotides on the model angioplasty (rat and rabbit)

Males with normal pressure Wistar rats or new Zealand rabbits were anesthesia and made the incision for the removal of iliac artery. The artery was purified from the surrounding connective tissue and put French catheter - balloon Fogarty. The tank was pumped with air to expand the artery, and promoted three times back and forth to get dezodorirovannogo damage.

Oligonucleotide dissolved in 25% pluronic gel, directly inflicted around the selected area of the artery. The wound was closed and animals were scored after 21 days. Carried out histomorphometrical analysis sections dezendothelization arteries and measured the inner and middle areas. The percentage of proliferation was determined (as indicated in the table.4 and 5).

Throughout the description assumed that the expression "PEFC is Telenesti LAST ID.

Example 5.

a) Activity in vitro of sense and antisense oligonucleotides on farnesyltransferase in C6 Gymnich cells of rats.

Cells were sown at a density of 5000 cells/plate and incubated in a medium supplemented with 5% horse serum and 2.5% fetal calf serum. After 24 hours the medium was replaced with medium without serum plus lipofectin and different oligonucleotides at a concentration of 5 μm for the implementation of transfection. After 5 hours of incubation the medium was replaced with normal, therefore, containing 15% horse serum and 2.5% fetal calf serum. Then the incubation was continued for 72 hours at 37oC. Cell proliferation was assessed by the number of cells after trypsinization monolayer, using the counter colter model ZM (see tab.6).

b) the Course over time of action of antisense oligonucleotide-subunit of farnesylpyrophosphate.

Cells were treated as described above, the counting of cells produced in parallel samples from control and treated with oligonucleotides cups on 3, 7 and 14 day. The p value was < 0.05% in each of the 3 days of the experiment.

Example 6. The study of the antiproliferative actions on glioblastoma in rats.5cells in 3 μl phosphatebuffered saline, prepared using trypsinization. We have previously observed in rats, which were scored in the days following the implantation of the tumor that the average time of survival was 24 days. Histological analysis of the brain obtained from all animals revealed that the implantation of the tumors was successful in 100% of cases. Two hours prior to slaughter all rats were injected with 40 mg BrdU. Animals were scored by decapitate. The whole brain was removed from all animals and were fixed by immersion in 70% ethanol for 2 days at 4oC. the Proliferation of the tumor was determined by cytofluorometric analysis biparametric DNA (BrdU) the two hemispheres of the brain (see tab.8).

Example 7. Preparation of pharmaceutical compositions.

Compounds according to the invention can be dried and used in dried form without additional additives, or used, for example, in the form of liposomes. Liposomes can be prepared by any conventional method known to the specialists.

a) freeze-Dried form.

Powder lyophilized oligonucleotide according to the invention can be used without any additives and, thus, the composition contains 100% of the oligonucleotides. This form of composition can be introduced locally at a dose of 5 mg/kg/day.

b) a Solution of cationic liposomes.

Liposomes prepared using the oligonucleotides according to the invention in the form p CLASS="ptx2">

Concentration is 10 mg antisense oligonucleotides per 1 ml solution. This solution can be administered at a dose of 1-10 mg/kg/day.

Sequence listing

Information on PET ID N 1

(1) sequence Characteristics:

(A) length: 12 base pairs

(B) type: nucleotide

(C) number of strands: single

(D) topology: linear

(IV) Antisense: Yes

(XI) sequence Description: PET ID N 1

AGAAGCCATG AT

(2) Information for TH ID N 2

(1) sequence Characteristics:

(A) length: 12 base pairs

(B) type: nucleotide

(C) number of strands: single

(D) topology: linear

(IV) Antisense: Yes

(XI) sequence Description: PET ID N2

GGACGTGACT GT

(2) Information for TH ID N3

(1) sequence Characteristics:

(A) length: 12 base pairs

(B) type: nucleotide

(C) number of strands: single

(D) topology: linear

(IV) Antisense: Yes

(XI) sequence Description: PET ID N 3

AAGGACTAGC AG

(2) Information for TH ID N 4

(1) sequence Characteristics:

(A) length: 12 base pairs

(B) type: nucleotide

(C) number of circuits: single

(D) topolo the Information TH ID N 5

(1) sequence Characteristics:

(A) length: 12 base pairs

(B) type: nucleotide

(C) number of strands: single

(D) topology: linear

(IV) Antisense: Yes

(XI) sequence Description: PET ID N 5

CCCGTCGTCC AT

(2) Information for TH ID N 6

(1) sequence Characteristics:

(A) length: 12 base pairs

(B) type: nucleotide

(C) number of strands: single

(D) topology: linear

(IV) Antisense: Yes

(XI) sequence Description: PET ID N 6

CTGTCCCTGT AC

(2) Information for TH ID N 7

(1) sequence Characteristics:

(A) length: 12 base pairs

(B) type: nucleotide

(C) number of strands: single

(D) topology: linear

(IV) Antisense: Yes

(IX) sequence Description: PET ID # 7

ACTTCTCTCT CC

(2) Information for TH ID N 8

(1) sequence Characteristics:

(A) length: 12 base pairs

(B) type: nucleotide

(C) number of strands: single

(D) topology: linear

(IV) Antisense: Yes

(XI) sequence Description: PET ID N 8

ACTTGGTCCT AA

(2) Information for TH ID N 9

(1) sequence Characteristics:

(A) length: 12 pairs osnovni: Yes

(XI) sequence Description: PET ID N 9

GCCATCATTC TG

(2) Information for TH ID N 10

(1) sequence Characteristics:

(A) length: 12 base pairs

(B) type: nucleotide

(C) number of strands: single

(D) topology: linear

(IV) antisense: Yes

(XI) sequence description: PET ID N 10

GATCTGGACC AC

(2) Information for TH ID N 11

(1) sequence Characteristics:

(A) length: 12 base pairs

(B) type: nucleotide

(C) number of strands: single

(D) topology: linear

(IV) Antisense: Yes

(XI) sequence Description: PET ID N 11

CTCAATAGCA TC

(2) Information for TH ID N 12

(1) sequence Characteristics:

(A) length: 12 base pairs

(B) type: nucleotide

(C) number of strands: single

(D) topology: linear

(IV) Antisense: Yes

(XI) sequence Description: PET ID N 12

GTTTTTGGGG TG

(2) Information for TH ID N 13

(1) sequence Characteristics:

(A) length: 12 base pairs

(B) type: nucleotide

(C) number of strands: single

(D) topology: linear

(IV) Antisense: Yes

(IX) sequence Description: PET ID N 13

TCTCACATCC TC

(2) the entrepreneur: nucleotide

(C) number of strands: single

(D) topology: linear

(IV) Antisense: Yes

(XI) sequence Description: PET ID # 14

TTGTAAGAAC TG

(2) Information for TH ID N 15

(1) sequence Characteristics:

(A) length: 12 base pairs

(B) type: nucleotide

(C) number of strands: single

(D) topology: linear

(IV) Antisense: Yes

(XI) sequence Description: PET ID # 15

GAAGTGCTTC TC

(2) Information for PET ID # 16

(I) sequence Characteristics:

(A) length: 12 base pairs

(B) type: nucleotide

(C) number of strands: single

(D) topology: linear

(IV) Antisense: Yes

(XI) sequence Description: PET ID # 16

GCCTCTTTC AG

(2) Information for TH ID N 17

(I) sequence Characteristics:

(A) length: 12 base pairs

(B) type: nucleotide

(C) number of strands: single

(D) topology: linear

(IV) Antisense: Yes

(XI) sequence Description: PET ID N 17

GGCATCTGTC AG

(2) Information for TH ID N 18

(I) sequence Characteristics:

(A) length: 12 base pairs

(B) type: nucleotide

(C) number of strands: single

(D) topology: linear

(IV) EN 19

(I) sequence Characteristics:

(A) length: 12 pairs

(B) type: nucleotide

(C) number of strands: single

(D) topology: linear

(IV) Antisense: Yes

(XI) sequence Description: PET ID N 19

GAACTGACAC AC

(2) Information for TH ID N 20

(I) sequence Characteristics:

(A) length: 12 base pairs

(B) type: nucleotide

(C) number of strands: single

(D) topology: linear

(IV) Antisense: Yes

(XI) sequence Description: PET ID N 20

ACGATCACAT CA

(2) Information for TH ID N 21

(I) sequence Characteristics:

(A) length: 12 base pairs

(B) type: nucleotide

(C) number of strands: single

(D) topology: linear

(IV) Antisense: Yes

(XI) sequence Description: PET ID N 21

ATCAACATGC AG

(2) Information for TH ID N 22

(I) sequence Characteristics:

(A) length: 12 base pairs

(B) type: nucleotide

(C) number of strands: single

(D) topology: linear

(IV) Antisense: Yes

(XI) sequence Description: PET ID N 22

CTGCATATCG AC

(2) Information for TH ID N 23

(I) sequence Characteristics:

(A) length: 12 base pairs


(XI) sequence Description: PET ID N 23

CAGTGCACCA GC

(2) Information for TH ID N 24

(I) sequence Characteristics:

(A) length: 12 base pairs

(B) type: nucleotide

(C) number of strands: single

(D) topology: linear

(IV) Antisense: Yes

(XI) sequence Description: PET ID # 24

CTGCAGCCTC GG

(2)Information for TH ID N 25

(I) sequence Characteristics:

(A) length: 12 base pairs

(B) type: nucleotide

(C) number of strands: single

(D) topology: linear

(IV) Antisense: Yes

(XI) sequence Description: PET ID N 25

ACTCTCTGGA CC

(2) Information for TH ID N 26

(I) sequence Characteristics:

(A) length: 12 base pairs

(B) type: nucleotide

(C) number of strands: single

(D) topology: linear

(IV) Antisense: Yes

(XI) sequence Description: PET ID N 26

CAAGAATCCT CG

(2)Information for TH ID N 27

(I) sequence Characteristics:

(A) length: 12 base pairs

(B) type: nucleotide

(C) number of strands: single

(D) topology: linear

(IV) Antisense: Yes

(XI) sequence Description: PET ID N 27

ACATCTGCTC TG

(2) Infolytica

(C) number of strands: single

(D) topology: linear

(IV) Antisense: Yes

(XI) sequence Description: PET ID # 28

TCTGTACTCG TC

(2) Information for TH ID N 29

(I) sequence Characteristics:

(A) length: 12 base pairs

(B) type: nucleotide

(C) number of strands: single

(D) topology: linear

(IV) Antisense: Yes

(XI) sequence Description: PET ID # 29

CTACAGTACA GC

(2)Information for TH ID N 30

(I) sequence Characteristics:

(A) length: 15 base pairs

(B) type: nucleotide

(C) number of strands: single

(D) topology: linear

(IV) Antisense: Yes

(XI) sequence Description: PET ID N 30

CCCGTCGTCC ATAGG

(2) Information for TH ID N 31

(I) sequence Characteristics:

(A) length: 18 base pairs

(B) type: nucleotide

(C) number of strands: single

(D) topology: linear

(IV) Antisense: Yes

(XI) sequence Description: PET ID N 31

CCCGTCGTCC ATAGGGGA

(2) Information for TH ID no 32

(I) sequence Characteristics:

(A) length: 21 base pair

(B) type: nucleotide

(C) number of strands: single

(D) topology: linear

TH ID N 33

(I) sequence Characteristics:

(A) length: 15 base pairs

(B) type: nucleotide

(C) number of strands: single

(D) topology: linear

(IV) Antisense: Yes

(XI) sequence Description: PET ID # 33

GGACGTGACT GTTTC

(2) Information for TH ID no 34

(A) length: 18 base pairs

(B) type: nucleotide

(C) number of strands: single

(D) topology: linear

(IV) Antisense: Yes

(XI) sequence Description: PET ID # 34

GGACGTGACT GTTTCCAC

(2) Information for PET ID # 35

(I) sequence Characteristics:

(A) length: 21 base pair

(B) type: nucleotide

(C) number of strands: single

(D) topology: linear

(IV) Antisense: Yes

(XI) sequence Description: PET ID # 35

GGACGTGACT GTTTCCACTG A

(2)Information for PET ID # 36

(I) sequence Characteristics:

(A) length: 24 base pairs

(B) type: nucleotide

(C) number of strands: single

(D) topology: linear

(IV) Antisense: Yes

(XI) sequence Description: PET ID # 36

GGACGTGACT GTTTCCACTG AGTC

1. Oligonucleotide selectively hybridities with the gene or transcription products for the subunits isoprenylated the activity of one or more grounds, selected from A (adenine), T (thymine), C (cytosine) and G (guanine);

About is a sequence selected from

R is absent or is a sequence of one or more bases selected A, T, C or g

2. Oligonucleotide under item 1, characterized in that it's hybrid gene of reproduktionsmedizin-and/or-isoprenyl-protein-transferring enzyme.

3. Oligonucleotide under item 1 or 2, characterized in that isoprenyl-protein transferase is selected from farnesyl-protein transferase, geranyl-geranyl-protein transferase type 1 and geranyl-geranyl-protein transferase type 2.

4. The oligonucleotide according to any one of the preceding paragraphs, characterized in that it includes 2 - 50 units.

5. Oligonucleotide under item 4, characterized in that it comprises from 10 to 20 units.

6. Oligonucleotide under item 5, characterized in that it comprises from 10 to 20 units.

7. Oligonucleotide under item 6, characterized in that it has the formula:

8. The oligonucleotide according to any one of the preceding paragraphs, characterized in that it has a modified skeleton.

9. Oligonucleotide under item 8, characterized in that at least one of the nucleotide bases modified.

1 is rmatio.

11. Oligonucleotide under item 8, characterized in that at least one of the linking groups is modified.

12. Oligonucleotide under item 8, characterized in that one or both of the position of the 5' and 3' modified.

13. Oligonucleotide under item 12, characterized in that one or more of positions 5' and 3' modified by substitution of a hydrophobic or a protecting group.

14. Pharmaceutical composition having anti-proliferative activity, containing as active ingredient an effective amount of at least one of the oligonucleotide according to any one of the preceding paragraphs in a mixture with a pharmaceutically acceptable diluent and/or carrier suitable for the chosen route of administration.

 

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The invention relates to medicine, in particular to Oncology and for the correction of the depression of hematopoiesis due to chemoradiation therapy

The invention relates to imidazolidinyl macrolides (substances with macrocyclic Laktionova ring), which are useful for mammals in the treatment of autoimmune diseases (such as juvenile diabetes or newly developed diabetes, multiple sclerosis and rheumatoid arthritis, liver disease, inflammation of the choroid eyeball, allergic encephalomyelitis, and glomerulonephritis), immunosuppression, infectious disease treatment and/or prevention of rejections of foreign bodies in transplantation (e.g., transplants, including xenotransplantation, bone marrow, kidney, liver, heart, skin, small intestine, and islet cells of the pancreas), when local treatment of skin diseases associated with inflammation or with an increased proliferation of cells, and cutaneous manifestations immunostimulating diseases (such as psoriasis, diffuse neurodermatitis, contact dermatitis, and other eczematous dermatitises, seborrhoeic eczema, red flat zoster, utricularia vulgaris, the bubble pemphigoid, congenital bullous bullosa, urticaria, angioedema, vasculitis, erythema, skin tinyline leukocytosis, lupus or focal alope the requirement of the respiratory tract, in particular asthma, inflammation of mucosa and blood vessels and infections caused by a virus cytomegaly, when the resistance of microorganisms to the action of drugs, idiopathic thrombocytopenic Purpur, chronic recurrent aphthous stomatitis (Behcet's disease), conjunctivitis, granulomatous disease (Crohn's disease), corroding ulcer of the cornea (Morena), inflammation of the choroid eyeball, acute intraocular inflammation and/or liver problems caused by ischemia

The invention relates to new N-substituted [2R, 3R (2'R, 3'R), 6R, 7S, 8S, 9R, 10R]-3-(2',3'-dihydroxyphenyl-2'-yl)-7-[(2,6-dideoxy-3-C-methyl-3-O--L-RIBO-hexopyranosyl)-oxy] -9-[(3,4,6-trideoxy-3-amino-B-D-Xylo-hexopyranosyl)-oxy] -2,6,8,10,12-pentamethyl-4,13-dioxabicyclo [8,2,1] -tridec-12-EN-5-he-connections with metalinguistically properties, to their salts, the acid products of accession, as well as to pharmaceutical remedies containing these compounds and methods and intermediate products for their production

The invention relates to methods for furostanol glycosides from plant material with antioxidant activity in comparison with structural analogue with similar biological properties, and thereby expands the Arsenal of tools that can be used in medicine as a therapeutic agent

The invention relates to Virology and relates to new biologically active compounds, namely salts 5 N-phosphonate 3'-azido-3'- deoxythymidine General formula given in the description

The invention relates to medicine, namely to kardiologii, and can be used in the treatment of chronic ischemic heart disease
The invention relates to chemical-pharmaceutical industry, namely the method for producing a non-narcotic analgesic-analgin, analgesic, anti-inflammatory and antipyretic action, hard gelatin capsules

FIELD: medicine.

SUBSTANCE: method involves carrying out hernia removal in intralaminar way. Posterior longitudinal ligament defect is covered with Tacho-Comb plate after having done disk cavity curettage. Subcutaneous fat fragment on feeding pedicle is brought to dorsal surface of radix and dural sac.

EFFECT: enhanced effectiveness of treatment; reduced risk of traumatic complications.

1 dwg

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