Anti-tumor and antiviral peptides

FIELD: chemistry of peptides, medicine.

SUBSTANCE: invention relates to preparing new peptides possessing immunomodulating, anti-proliferative, anti-tumor and antiviral activity. Invention proposes new peptides comprising up to 30 amino acid residues of the general structural formula: X1-Trp-Gly-Gln-X2 wherein X1 is taken among the following group: -His-Gly-Val-Ser-Gly-, -His-Gly-Gly-Gly-, -His-Val-Gly-Gly-, -His-Gly-Gly-Gly-Gly-, and -Gln-Gly-Gly-Gly-Gly, or absent; X2 is taken among the following group: -His-Gly-Thr-His-Gly, -Gly-Gly-Thr-His-Gly, -Pro-His-Val-Gly-Gly, -Pro-His-Gly-Gly-Gly, -Pro-His-Gly-Gly-Gly-Trp-Gly, -Gly-Gly-Gly-Thr-His-Ser, or absent.

EFFECT: valuable medicinal properties of peptides.

8 cl, 5 tbl, 5 dwg, 6 ex


The technical field.

The present invention relates to peptides and proteins, anticancer and antiviral activities, as well as to medicines on the basis of them.

The level of technology

Known antitumor peptides from the group of bleomycin (NI Perevozchikova. Clinical chemotherapy of neoplastic diseases. M, Medicine, 1976, S. 100-103). Bleomycine have a direct cytotoxic effect on tumor cells, but the possibility of their application in the clinic is limited pronounced side effects, primarily by the lungs and kidneys.

It is known the use of recombinant proteins from a group of interferons as activators of antitumor immunity and inhibitors of proliferation of tumor cells. Interferons are used to treat multiple myeloma (Zee et al., J. Clin. Oncol., 1998, 16, 8, p. 2834-2839), Hodgkin's disease (Aviles et al. Leuk. Lymphoma, 1998, 30, 5-6, p. 651-656), myeloid leukemia (Gilbert, Cancer, 1998, 83, 6, p.1205-13). However, the high cost interferon makes them unaffordable for wide clinical use. Another limitation are side effects associated with possible pyrogenalum, immunogenicity and other undesirable properties of recombinant interferon.

Known proposals for the use of peptide inducers of apoptosis as a potential protivoopuhulevyh drugs the the ATA (Rutledge, Chin and Schepartz Current Opinion in Chemical Biology, 2002, 6 p. 479-485). However, the clinical prospects of this direction remain unexplored. Currently under development and clinical trials as protivoopuhulevyh funds is the number of protein drugs cytokine nature (S.K. Narula, R. Coffman, eds. New cytokines as potential drugs, Birkhauser Verlag, Basel, 2000, 141 pp.). Best known use of interleukin-2, however, the high toxicity and cost of recombinant interleukin-2 limit its use in a wide Oncology practice.

It is known the use of proteins hemocyanine and allforyou as activators of the immune response and antitumor agents (U.S. patent No5231081).

Despite the above and other developments described in the literature, treatment of cancer in many cases is ineffective and almost always highly toxic and expensive. Therefore, the search for new approaches to the treatment of tumors remain one of the most acute problems of modern medicine.

Known immunomodulatory peptides - alloferon (patent of Russian Federation No2172322). The main field of application of allopurinol is the treatment of viral infections. At the same time there is information about the anticancer properties of allopurinol based on the activation mechanisms protivo the Holevo immunity - interferons and natural killer cells (Chernysh et al., Proceedings of National Academy of Science, 2002, 99, p. 12628-12632). Alloferon are the closest analogues of the present invention according to the chemical structure and mechanism of action.

The essence of the invention.

Experimental studies of the antitumor activity of alloferon showed that this peptide inhibits the growth of syngeneic tumor transplant in mice and on this basis can be classified as promising anticancer drugs. The effect of alloferon is implemented at the level of system response of the organism to transplantirovannam tumor. At the same time, at the cellular level, the effect of alloferon on the proliferation of the tumor is more complicated. In particular, in vitro experiments showed that alloferon, depending on the concentration in the culture medium, can inhibit (in high concentrations), and boost (low concentration) proliferation of tumor cells. The presence of growth stimulating activity limits the use of alloferon for therapy of tumors, where the suppression of proliferation of malignant cells is a major goal of treatment.

This isbreene is to develop drugs that are keeping immunomodulatory mechanism of action of alloferon, at the same time would have the lower growth stimulating activity and enhanced antiproliferative and cytotoxic activity against tumor cells.

To this end developed a new family of peptides that differ from allopurinol and other biologically active compounds of structure, mechanism of action and achieve therapeutic effect.

The proposed connection group refers to a linear peptides, the structure of which is described by the following structural formula:

X1Trp Gly Gln X2(1)

where X1missing or contains at least 1 amino acid,

X2missing or contains at least 1 amino acid.

When developing the present invention, the basic structure was used for the peptide shown in Table 1 under the name allostatic 1 (SEQ ID NO 1). Allostatic 1 was synthesized by the method of solid-phase synthesis and used to study the biological and therapeutic activity of the proposed peptides. Research, the results of which are summarised in the following examples, showed that this peptide has anti-tumor activity based on direct inhibition of proliferation of tumor cells and strengthen certain parts of antitumor immunity.

Computer analysis of the database on the structure and properties of proteins and peptides found that this compound belongs to a new previously unknown family of biologically active peptides. The original structure comprises the protected peptides provides new technical achievement level opportunities for effective suppression of tumor growth and treatment on this basis of cancer.

Analysis of homology of amino acid sequences of allocating 1 and known proteins and peptides made using the program Blast search on materials Swissprot database revealed a number of structural analogues of the proposed peptides. These data are summarized in Table 1.

The identified sequences with high homology with respect to allocatio 1 belong to homogeneous from the point of view of structure, function and origin of the group of compounds prinovis proteins (PrP). Prion proteins (prions) are produced by cells of various tissue facilities of many animal species, including humans and other mammals. The function of the normal prion remain poorly studied. At the same time, it is known that under certain conditions prions can undergo a conformational change, in which there is abnormal scrapie isoform responsible for the development of some neurodegenerative diseases. Mature prion protein usually contains more than 200 amino acid residues. Pathological prion properties associated with fragments homologous to the fragment 114-134 PrP I bull, in particular amyloid hydrophobic segment AGAAAAGA this fragment (Kourie, J.I. Chem. Biol. Interact., 2001, 138, 1-26; Taylor, S.C., Green, K.N., Smith, I.F. & Peers, C. Am. J Phsiol. Cell Physiol., 2001, 281, 1850-1857). Allostatic 1 homologous repetitive plots 64-75, 72-83, 80-91, 87-98, 96-108 and structurally completely different from the plot 114-134 PrP I. the Close structural similarity of these sites and the proposed peptides (for example, in the area 96-108 PrP I bull coincide with allocation 11 amino acids from the 13 or 84%) implies a similarity of biological activity. Therefore, with high probability we can assume that the fragments of mammalian prions, homologous offer antitumor peptides also have similar anti-tumor activity. The probable mechanism of antitumor action of these fragments is unknown, however, there are data showing that prions are relevant to the regulation of the activity of T-lymphocytes (Mabbott, N.A., Brown, K.L., Manson, J. & Bruce, M.E. Immunology, 1997, 92, p.161-165). T-lymphocytes, in turn, play a key role in the reactions of antitumor immunity.

Structural and functional similarities with fragments of mammalian prions allows you to isolate the potentially variable sites of the proposed sequence of peptides, in which replacement of the composition and sequence of amino acids will not have a significant impact on the functional properties of the molecule as a whole. Taking into account the distribution of the variable and conservative areas of the amino acid sequences given in Table 1, the overall structure of the structural formula (1) includes two variable zone X 1and X2separated conservative sequence of the amino acids tryptophan, glycine and glutamine (Trp-Gly-Gln). Variable plot X1may be missing or contain up to 5 or more amino acids. Variable plot X2may be missing or contain up to 7 or more amino acids. Moreover, the peptides can be part of a larger amino acid sequence as a functionally important part of other polypeptides and proteins, such as Pranovich proteins with chain length up to 250-300 amino acids.

Connection of the proposed structure represented by allocation 1, synthesized using solid phase synthesis method and characterized using high-performance liquid chromatography and mass spectrometry. They can be obtained in the form of esters, salts, amides, or other pharmaceutically acceptable derivatives. In particular, allostatic can be included in larger proteins, polypeptides without changing their pharmacological activity or to give them new properties. It is also clear that the pharmaceutically acceptable derivatives allocatin can be obtained by chemical modification of side radicals or end sections of amino acids forming part of allocatin. In addition to chemical synthesis, the peptides offer you floor the AMB by means of genetic engineering or extract them from natural sources. With the aim of genetically engineered receipt of the proposed peptides can be synthesized nucleotide sequence encoding the amino acid sequence of allocation, these nucleotide sequences can be by means of a suitable vector is introduced into the genome of the host cell, and the transformed thus, the cells used for the synthesis of the proposed peptides. It is also clear that these nucleotide sequences and vectors, and transformed their cells can be introduced into the body for the synthesis of the proposed peptides directly in the body.

Other structural analogues of the proposed peptides are alloferon, General structural formula of which is given in the patent of Russia № 2172322. The results of the comparative analysis of structural formulas allopurinol and offer peptides, allocation, are shown in Tables 2 and 3. In Table 2 are mapped structure alloferon 1 (SEQ ID NO 12) and allocating 1 (SEQ ID NO 1), two typical representatives compare families of peptides. From the comparison it is seen that these peptides differ in the amino acids at positions 6 and 11, presented at alloferon 1 histidine and valine, and allocating 1 tryptophan and threonine, respectively. Positions 6 and 11 comprise part and characteristic of all allopurinol according to the patent of Russia № 212322. Replacement of amino acids in these positions on tryptophan and threonine lead to the desired change in biological activity and therapeutic effect, as shown in the examples below. Comparison of General structural formulas (table 3) shows that the composition of the conservative areas and the location of the variable regions comprising molecules allocation and allopurinol qualitatively different. On this basis, they can be attributed to two different families of peptides.

A study of the biological and Toxicological characteristics of allocating 1 show that the peptides of this group are not toxic to individual cells and the whole organism of experimental animals. Thus, in example 2 the results of experiments with cell lines R, according to which the concentration of allocating 1 in 10000 times the minimum therapeutically effective concentration, does not have cell cytotoxic activity. Research, the results of which are shown in examples 4-6, showed no signs of toxic effects of allocating in doses that provide a pronounced therapeutic effect. Thus, allostatic should be attributed to non-toxic compounds (group a classification of drugs).

Information confirming the possibility of carrying out the invention.

Note the p 1. Synthesis of allocating 1

A peptide consisting of 13 amino acids corresponding to the structure of allocating 1, was synthesized by the method of solid-phase synthesis on an automated multi-channel synthesizer Multisyntech GmbH, Witten, using Fmoc-(N-[9-fluorenyl]methoxycarbonyl)-substituted amino acids. Purification of the synthesized peptide was carried out by obetovannoi HPLC on a chromatograph Shimazu LC8 with column Chromasil C18, 10 mm, the purity of the obtained peptide also controlled by HPLC (figure 1). The correctness of the synthesis confirmed by mass spectrometrically method MALDI-TOF instrument Finnigan TSQ 7000 (figure 2). Experimentally established the mass of the peptide corresponds to the calculated differences are within the errors of measurement.

Example 2. The influence of allocating on the proliferation of tumor cells in vitro

The goal of the experiments described in this section is a comparative analysis of the impact of allocating and alloferon on the proliferation of tumor cells. Compared the effect of allocating 1 and alloferon 1 in concentrations of 0.001, 0.01, 0.1, 1 and 10 µg/ml on proliferative activity in mass culture tumor cell line RD. In wells of 24-well plates were sown at 5000 cells suspended in 2 ml RPMI medium 164. In the experiments used a medium containing 5% fetal calf serum production company "Bilat". Preparations were made in moons and 0.2 ml of the same medium immediately after seeding of the cells, in the control contributed an equivalent amount of medium without drugs. The number of cells in 1 ml of incubation medium were determined using camera Goryaeva. On the basis of 3 independent determinations was calculated the average number of cells in 1 ml of incubation medium through 21, 44, 90 and 114 hours after the start of the experiment. Figure 3 presents a typical picture of the impact of allocating and alloferon on the dynamics of the growth of tumorous cells. As a criterion of the antiproliferative activity of drugs here the selected value of the ratio of growth of the population over 90 hours of observation, defined as the ratio of the number of cells per well at the beginning and end of the incubation period. During this period, control the number of cells increased by about 30 times. In the presence of drugs, the number of cells and, accordingly, the rate of proliferation was decreased dose-dependent manner. However allostatic in the concentration range 0.001-1 μg/ml in 3-7 fold alloferon for antiproliferative activity. Allocation at a concentration of 10 μg/ml almost completely stopped the growth of tumorous cells in the observed period. Thus, this example demonstrates the presence of allocating antiproliferative activity and its advantage in this respect in comparison with allopurinol.

Example 3. The interaction of allocating and protivoop the left of cytotoxic drugs in vitro

In this example, the material showing the interaction of allocating and classical cytostatic agent, cyclophosphamide, regarding the suppression kopaganj activity of tumor cells. Figure kopaganj activity allows you to determine what proportion of tumor cells from the shared pool can give a viable clones and thus to participate in the growth and spread of tumors. The main objective of hemoterapia is to destroy these actively proliferating cells.

The method of setting the experiment consisted in the following. Cell lymphoma neoplasm mouse line RD were cultured in medium RPMI 1640 containing glutamine, gentamicin and 10% fetal calf serum "clone High". When setting experience in cell 24-hole culture of tablets made of 100 cells RD in 1 ml of medium of the composition. Immediately after that, the wells were made in 0.1 ml medium without verifiable drugs (control wells) or with drugs. Each version of the experiment was placed in three independent replicates. The number of clones was counted 7 days after the beginning of kultivirovanija.

As can be seen from Table 4, under the conditions of this experiment, about 15% of tumor cells formed a viable clones. Either cyclophosphamide or allocation, taken individually, do not have significant impact on the process of konyrov the deposits. At the same time, their combination significantly reduced the count of clonogenic activity of tumor cells is proportional to the dose of allocating.

This example shows that allocation has potential use in combination hemoterapia tumors in combination with cytotoxic drugs type of cyclophosphamide.

Example 4. Antitumor activity of allocating on the model of transplantable tumors in mice

Laboratory mice DBA-1 subcutaneously vaccinated 3000 syngeneic tumor cells lines RD. The next day the animals were divided into 4 experimental groups. In the first group, they were only allocating subcutaneously at a dose of 25 mcg on 4, 11 and 18 days after transplantation of tumor cells; in the second group, the combination of cytostatic drugs cyclophosphamide (0.56 mg), doxorubicin (0.036 mg) and vincristine (1.05 g) on the day of transplantacii, after 7, 14 and 21 days; in the third group of allocation and cytostatic combination according to the same scheme. In the fourth group (control) animals at the same time introduced the solvent (0.9% NaCl). In the control group palpable tumors at the site of transplantation of the cells began to appear after 20 days, 25 days all mice were typical subcutaneously located tumors ranging in size from 5 to 26 mm in diameter (figure 4). In the groups treated separately allocating or cytostatics, tumors appeared with a delay, a small part of W is animal tumors are not formed over the entire observation period. At the same time, the combination of allocating and drugs provided sharp and in many cases irreversible antitumor activity. In this group, only 40% of mice formed tumors during the follow-up period (P< 0.001 compared to control and P< 0.05 compared to the group treated only cytostatics). This example, like example 3, shows that allocation has a strong antitumor activity when used in combination with the means standard hemoterapia, widely used in the treatment of leukemia and other cancers.

Example 5. Immunomodulatory (interferonogenna) activity allocating Alloferon are immunomodulators, mechanism of action which involves the induction of the synthesis of interferon by peripheral blood leukocytes (Chernysh et al. Proceedings of National Academy of Science, 2002, 99, p. 12628-12632). One of the purposes of the present invention consisted in the preservation of the immunomodulating effect in the spectrum of biological activity of allocation. This example illustrates together with immunomodulating activity of allocating 1 on the model of induction of interferon synthesis by leukocytes in humans in vitro. Samples of donor blood was mixed with an aqueous solution of the test drug and the culture medium in a ratio of 1:1:8. The final concentration of drugs in the incubation mixture were 0 (control), 0.01, 0.1, 1 or 10 μg/ml in different variants of experience. This mixture is incubated for 24 hours at 37°in CO2thermostat. Then, blood cells were precipitated by centrifugation. After serial dilution of the resulting supernatant were placed in wells of 96-hole tablet containing a monolayer of the test cell culture L-41, and preincubator 24 h under the same conditions. Then the monolayer of cells was infected with vesicular stomatitis virus in a dose of 100 TPD (the dose that causes the death of 50% of the cell monolayer) and preincubation 18 h at 37°C. Then cells were stained with 0.1% solution of the dye crystal violet. The proportion destroyed by virus monolayer was determined by measuring the optical density of the extracted dye at a wavelength of 590 nm. The obtained values were compared with the effect of the reference drug interferon-alpha, and the resulting titer of interferon result obtained in units of (ME) antiviral activity of interferon-alpha. Figure 5 summarizes the results of the study blood samples 6 donors, taken in two analytical replicates (a total of 12 definitions for each point).

The results indicate that interferonogenna activity allocating and alloferon not significantly different. Therefore, allocation, acquiring specific properties, useful for its application as an antitumor ven the rata, at the same time retains the inherent alloferon together with immunomodulating activity. On this basis, allocation can be used in Oncology and other areas where this may be useful as a drug double action: direct (cytotoxic and antiproliferative effects, potentiation of the effect of cytostatic drugs) and indirect (immunomodulating).

Example 6. Antiviral activity of allocating

In studies of antiviral action of allocating as the model used lethal influenza infection in outbred white mice of both sexes weighing 14-16, used the influenza virus A/Aichi/2/68 (H3N2), adapted to white mice. Allocation and alloferon was dissolved in distilled water and was administered to animals at 0.25 ml subcutaneous injection of 25 μg per mouse (1.5 mg/kg of body weight). As a placebo in the control group was administered distilled water. To determine the antiviral activity of the drugs used in the prevention scheme introduction of a single injection of drugs for 24 hours before infection. The virus was injected animals intranasally under light ether anesthesia in a dose of 3 and 30 LD50. In each group the observations were taken on 10 mice. Observation of the animals was carried out for 14 days. Recorded mortality of animals in the control and experimental groups. The results of experimentpresented in Table 5. Both drugs were providing equally effective protection against lethal influenza infection in mice. Thus, allostatic retains antiviral activity characteristic of alloferon. On this basis, we can assume that allocation can be used as an anti-virus tools as alloferon. The most helpful instead of alloferon in the case of border States, combining viral and oncological pathology, such as tumors of viral etiology or treatment of viral infections in cancer patients.

Table 1

The homology sequence of the proposed peptide and Pranovich proteins of mammals.

Allostatic 1

PrP1 Trast

f 80-91
HisGlyGlyGlyTrpGlyGlnProHisGlyGly Gly

PrP1 Trast

f 96-108

PrP2 Trast

f 64-75

PrP2 Trast

f 72-83

PrP2 Trast

f 88-100

Prio bovin

f 96-108
HisGlyGlyGlyGlyTrp GlyGlnGlyGlyThrHisGly

Prio bovin

f 64-75

PrP Human

f 52-66

PrP Human

f 69-83

PrP Human

f 85-97
Conse the WM-sequence TrpGlyGln

Table 2

Comparative analysis of amino acid sequences alloferon 1 and allocating 1.

Allostatic 1

Alloferon 1

Table 3

CPA is a comparative analysis of the General structural formula allopurinol and allocation.

td align="center"> 21
Table 4

The combined effect of cyclophosphamide and allocating on the ability of the tumor cell line RD to the education of the child clones
MedicationConcentrationThe number of clones in

separate holes

Control-16161214,7 ± 1,3
Cyclophosphamide1.5 mcg/ml12191415,0 ± 2,1
Allostatic0.1 mg/ml21201418,3 ± 2,2
1 mcg/ml14191917,3 ± 1,7
10 mg/ml161517,3 ± 1,9
Cyclophosphamide + Allostatic1550 ng/ml + 0.1 mg/ml8898,7 ± 0,3
1550 ng/ml + 1 mg/ml66107,3 ± 1,3
1550 ng/ml + 10 mg/ml3443,7 ± 0,3

Table 5

Antiviral activity of drugs allocation and alloferon against influenza virus A/Aichi/2/68 (H3N2) on the model of lethal influenza infection in white mice.
MedicationThe dose of the virus, LD50Mortality of animals (Palo/infected PCs).The percentage loss,%Mortality is the sum of two doses of the virus,%
33/10 30

** The probability of difference from control P< 0,01

1. The peptide containing up to 30 amino acid residues characterized by the General structural formula:

X1Trp Gly Gln X2

or its pharmaceutically acceptable salts, or esters, or amides, where

X1selected from the group of His-Gly-Val-Ser-Gly-, His-Gly-Gly-Gly-, His-Val-Gly-Gly-, His-Gly-Gly-Gly-Gly - Gln-Gly-Gly-Gly-Gly or absent,

and X2selected from the group of-His-Gly-Thr-His-Gly, -Gly-Gly-Thr-His-Gly, Pro-His-Val-Gly-Gly, Pro-His-Gly-Gly-Gly, Pro-His-Gly-Gly-Gly-Trp-Gly, -Gly-Gly-Gly-Thr-His-Ser or absent.

2. The peptide according to claim 1, containing up to 20, preferably 5-15 amino acid residues.

3. The peptide according to claim 1, selected from the group consisting of





His - Val-Gly-Gly-Trp-Gly-Gln-Pro-His-Gly-Gly-Gly,




4. The peptides according to claim 1, having immunomodulatory activity.

5. The peptides according to claim 1, having antiproliferative activity.

6. The peptides according to claim 1, having antitumor activity.

7. The peptides according to claim 1, having the anti-Christ. virusnoi activity.

8. Pharmaceutical composition having immunomodulatory, antiproliferative, antitumor or antiviral activity containing peptides according to claim 1 or their pharmaceutically acceptable salts, their esters or amides, in combination with a pharmaceutically acceptable carrier.


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11 cl, 6 dwg, 4 ex

FIELD: bioorganic chemistry.

SUBSTANCE: invention provides somatostatin agonists of general formula: A1-cyclo{Cys-A2-D-Trp-A3-A4-Cys}-A5-Y1 (I), wherein A1 represents aromatic D- or L-α-amino acid selected from Phe, D-Phe, Tyr, D-Tyr, β-Nal, D-β-Nal, Cha, or D-Cha; A2 aromatic α-amino acid selected from Phe, Tyr, β-Nal, and Cha; A3 Lys or Orn; A4 β-hydroxyvaline, Ser, hSer, or Thr; A5 β-hydroxyvaline, Ser, hSer, or Thr; and Y1 represents NH2; amide nitrogen atoms of peptide groups and amine group of A1 in compound I are optionally substituted by methyl group, provided that at least one methyl group is available and that compound I cannot have following formula: D-Phe-cyclo{Cys-Phe-D-Trp-Lys-(N-Me-Thr)-Cys}-Thr-NH-2. pharmaceutically acceptable salts of compound I are also claimed.

EFFECT: expanded synthetic possibilities in peptide synthesis.

24 cl, 2 tbl, 18 ex

The invention relates to the field of biotechnology, specifically to peptides active in the attachment, respectiveiy and detaching cells, and can be used to study activity in the attachment of cells, mediated by different proteins of the extracellular matrix, to develop peptides, adhesion, and also for medicinal purposes

The invention relates to peptide compositions with delayed release, representing a compound (I) containing the compound (A) formula

and the polymer containing lactide links, glycolide links and links tartaric acids - which are found in the polymer at the next sootnoshenii: lactide units constitute from about 71% to about 73%, glycolide links from about 26% to about 28%; and the parts of tartaric acid from about 1% to 3%, and the amino group of the compound (a) relate ionic bond with the carboxyl groups of the acid units of the polymer; the particles of compound I, an average size of from about 10 microns to about 100 microns; pharmaceutical composition with delayed release and two methods of treatment of various diseases, including the introduction to the patient an effective amount of compound A, or microparticles

FIELD: medicine.

SUBSTANCE: method involves administering diacerine influencing DNA synthesis for reducing keratinocytes proliferation without changing their vital activity, inhibiting interleukines IL-1,IL-6 and α-TNF (tumor necrosis factor).

EFFECT: enhanced effectiveness of treatment.

11 cl, 7 dwg, 2 tbl