JPH04504581A - Fibroblast growth factors for the prevention and treatment of viral infections - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] For the prevention and treatment of viral infections Fibroblast growth factor used The present invention is caused by a virus known as an enveloped virus. Fibroblast growth factor (FG) used for the prevention and treatment of viral infections caused by Regarding F). Examples of such viruses include α-type herpesvirus. [Type 2 herpes simplex virus (H8v2) and water! E/band-shaped lupes]; β- or γ-type herpesviruses [cytomegalovirus, etc.]; Orthomyxovirus, influenza virus, etc.], paramyxovirus, influenza virus, etc. Respiratory syntium virus (I (RSV), etc.); skin fever and/or encephalitis The causative tropical virus Rosemuriki Forest Virus (SFV) and other tropical disease viruses (e.g. “Alpha”, rFl&yij, “ArelI&” group) or retroviruses [which are the cause of acquired immunodeficiency syndrome]; HIV virus and Moloney Sarcov [Mo1ooe7 S*+com*) ( MSV)].

To fight off infectious diseases caused by the above viruses (especially H5V2, etc.) Although much effort has been made, no truly effective drug has yet been found. .

Fibroblast growth factors include, for example, human and bovine basic fibroblast growth factors (bFG F) and human and bovine acidic fibroblast growth factor (aFGF).

These factors are potent agents against a wide variety of cells, including fibroblasts and endothelial ductal cells. Known as a mitogen. In particular, (to be precise, replication of vascular endothelial cells) Regarding vascular genetic effects (associated To date, applications in repair tissues have been mentioned.

In recent years, Kaoe+ and others have been linked to type 1 herpes simplex virus (H3V). disclosed that fibroblast growth factor and its analogues exhibit activity in Enns, '1991 24g, 1,410-1.4N). Its activity is Omi's H8V It is a very special virus that can only be found in this type of virus.

If the above growth factors attach to their specific cell receptors, they prevent virus entry. It will prevent the virus from binding to its receptors. □ Since H3V and H8v2 receptors are reported to be different (A, V Af+LNE etc., 1. Gea, Virolog 744, pp. 217-225 (19 79)), HS V, whether it is affected by growth factors on the type of virus. is unpredictable. This means that one drug is different for EISvl and HSV2. The fact that biochem , Bioph, Re+, Comm, lH6, L41.19g-203) will be confirmed.

Now, we have discovered that fibroblast growth factor (FGF) and its analogues are linked to the growth of certain viruses. It was discovered that infection can be prevented.

The present invention is a method for preventing viral infections caused by enveloped viruses. This invention relates to fibroblast growth factor (FGF) used for prevention and treatment. such will For example, α-type herpesvirus [type 2 herpes simplex virus] virus (H8v2) and chickenpox/zoster/herpes]; β or γ type herpes virus “cytomegalovirus, etc.”: Orthomyknvirus [influenza virus, etc.] virus, etc.], paramyxovirus [human respiratory syntium virus (HR) Tropical viruses that cause typhus fever and/or encephalitis [Semliki Forest virus (SFV) and other tropical disease viruses (F!4, ``Alpha'') , "NawiJ, belonging to rAreaaJ group viruses)"; or Letrow virus [HIV virus and Mouni-Sarcovirus that cause acquired immunodeficiency syndrome] (Moloa!7 Sarcoign (MSV)).

Specific examples of viruses for which the fibroblast growth factor of the present invention has been determined to be effective include: is a type 2 herpes simplex virus H8v2, a human respiratory infection. virus (HRSV), Semliki forest virus (SFV), acquired immune system Moloney Sarcoma (MSV), a virus that causes epidemic syndrome, causes Examples include viruses.

The fibroblast growth factor (FGF) of the present invention is a basic (b) FGF (human or c), acidic (a) FGF (human or bovine), or bFGF or a FGF types It can be a likeness.

The above growth factors, human and bovine bFGF, and aFGF are known factors. be. for example,! 'CT 1086107595 and PCT V (lIt7101 728; European Patent Application No. 226.181, European Patent Application No. 237,966, European Patent Application No. 2 59.953, and various scientific papers (for example, Science Vol. 233, 56 Pages 5-54B, August 1, 1986; εa+b.

Journal Vol. 5-10, 2, pp. 523-2.528, 1986; Biochemika Le & Bio Physical Red, Communication Volume 140 Fish 3. Pages 874-880, 1986, Volume 133, Run 2. 554-56 2 pages, 1985; Science Vol. 230, pp. 1.385-1,388, 1985 (December 20, 2013).

The terminology used to define the FGF factor referred to in the present invention is 581 (3) Schradet and Lubke's "Ding be Peplid + sJ Academic Cup This is what was shown by Les (1965). There, according to the customary expression, Residues with a free α-amino group at the N-terminus are on the left; Residues with groups are on the right.

Therefore, for example, human bFGF has the sequence shown below at 146 (1 Pro Al a Leu Pro Glu sp Gay Gly Sar Gay Al a　Phe　Pro　Pro　Gly　H3-■ Phe Lys 8sp Pro Lys Arg Leu Tyr Cys Lys　Asn　Gay　Gly　Phe　Phe　r,e■ Arg Ile H’hs Pro Asp Gly Arg Val 8sp Gly Val Arg Glu Lys Ser ＾5■ 11e Lys Gly Val Cys Ala enter sn Arg Tyr Lau Ala Met Lys Glu 8 Sp GIY 8r Leu G lu ser Asn Asn’ryr Asn Thr Tyr, %rg Sar　Arg　Lys　Tyr　T■■ Ser Trp Tyr Val Ala Leu Lys Enter rg Thr Gly Gln Tyr Lys Leu Gay 5erLys Thr G ay Pro Gly Gin Lys Ala Ile Leu PheLa u Pro Met Ser Ala bovine bFGF has almost the same sequence . However, human bFGF [Thr amino acid at position 12, Ser amino acid at position 128] The amino acids are substituted with 5erSPr+) in bovine b FGF, respectively. Similar to FGF, the human bFGF molecule contains all 11 of the following 11 amino acids: or can have an N-terminal (extended) extension containing a portion.

(i) Gly-τbr-Met-Ala-Ala-G17-3! y-11e- Tht-Thr-Leu, e.g., especially the following nine amino acids, (ii) Met-Alx-Alg-G17-3er-11e-Thr-Thr -Lea, or the next 8 ((eyes) ^1a-Ala-G17-5er-11e- Thr-Thr-Leu, or the next 7 a (eyes) ^1a-G17-3er- 11e-Th+-Thr-Leu 146 amino acids of human and bovine bFGF The molecule may also lack one or more amino acid residues at the N-terminus.

Human aFGF is a polypeptide having the amino acid sequence shown below.

Phe Asn Leu Pro Pro Gly Eight Sn Tyr Lys Lys Pro Lys Leu L@’J Tyr Cy■ Ser　Asn　Gly　Gly　His　Phe　Leu　Arg　Ile　 Leu Pro Asp Gly Thr Val AspGly Thr A rg enter sp Arg Ser enter sp Gln His Ice Gln L eu Gln Leu Ser ^1aGlu Ser Val Gly Gl u Val Tyr Ile Lys Ser Thr Glu Thr Gl y Gln TyrLeu Enter 1a Met Asp Thr Asp Gly Leu l4cJ Tyr Gly Ser Gln Thr Pro 8s ■ G’iu Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn Hls Tyr Asn Th■ loo 110 Tyr Engineering Sir Lys Lys Hls Enter 1a Glu Lys Asn　Trp　Phe　Val　Gly　Leu　LysLys　8sn　G ly Ser Cys Lys Arg Gly Pro Enter rg Thr H is Tyr Gly Gln Lys bovine aFGF also has the sequence shown below. It is a polypeptide of 140 amino acids. It is highly compatible with human aFGF. There is same sex.

Ser Asn Gly Gly Tyr Phe Leu Arg Engineering 1e Leu Pro Asp Gly Thr Val AspGly Thr L ys Asp Arg Ser lsp Gln 1 (is Eng 1e Gin Leu　Gln　Lea　：ys　Al■ So 60 Glu Ser Ile Gly Glu Val Tyr Engineering Lys S ar Thr Glu Thr Gly Gln PhaLeu Ala Me t Asp Thr Asp Gly Leu I, eu Tyr Gly S er　Gin　Thr　Pro　As■ Glu　Glu　Cys　Leu　Phe　Leu　Glu　8rg　Leu　 Glu Glu Asn His Tyr Asn Thrloo’ 110 Tyr Ser　Ser　Lys　Lys　His　Ala　Glu　Lys　H is Trp Phe Val Gay Leu LysLys sn Gl y Arg Ser Lys Leu Gly Pro Arg Thr Hi s Pha Gay Gln LysDo 140 Aha Ila Leu Phe Leu Pro Leu Pro Val Ser　Ser　Asp.

Both human and bovine aFGF molecules also have the same structure as described above for bFGF molecules. It can undergo extensions and deletions at the N-terminus.

Fibroblast factors of the invention may also be amidated at the C-terminus.

Analogs of the above-mentioned fibroblast factors are, according to the invention, for example the complete FGF molecule. any fragment (possibly amidated) of It may be something that can be combined.

Examples of such fragments are disclosed in European Patent Application No. 246,753. It is. For example, they are particularly useful for both human and bovine FGF nos. 93-120. , 97-120, 100-120, 103-120, 103-146 ．． 106-115. 106-118.　106~120゜106~125. 106-130. 106~N5. 106-140. 106-146 and A polypeptide consisting of the amino acid sequence from positions 107 to 110 (both free form and amidated form).

Analogs of fibroblast growth factors of the present invention include substitutions and/or deletions of one or more amino acids. Mutants (amino acids) derived from the above FGF polypeptides or analogs thereof by (which may or may not be a form of It is also possible to maintain equidominance of the ability to combine.

Thus, for example, amino acid position 112 is Thr or Set: 12 8th place is Ser or Pro; 113th place is Ala or Ser; 114th place The one in the fifth position is Met or Trp; and the fifth one is Phe or Tyr. Can be done. Different forms of FGF (e.g. different types of extension at the N-terminus or Mixtures of the aforementioned variants derived from deletions are also considered within the scope of the invention. It should be done. The term "fibroblast growth factor" refers to all analogs mentioned above. However, it also refers to such mixtures.

As mentioned above, the growth factor according to the present invention is a known factor and therefore a known factor. can be prepared by the method. For example, recombinant DNA method (PCT WH6107 595, PCT WO37101728, and European Patent Application Publication No. 226.18 1, 237.966, and 259.953 (above). (same operations, etc.). FGF analogues (e.g. of the present invention) can be prepared using known techniques. FGF fragment) may be obtained. For example, the aforementioned European Patent Application Publication No. 246, 753 and the method of document disclosure listed therein (JAC58521 49 (1963)) can be used. .

Chemical synthesis consists of short amino acid sequences (for example, sequences of 40 or fewer amino acids). Preferred for fragment synthesis. On the other hand, preparation by recombinant DNA method (e.g. natural FGF molecules of sufficient length (e.g., containing 40 or more amino acids) or analogues thereof. preferred for the preparation of The antiviral activity of the fibroblast growth factor according to the present invention In order to illustrate the nature of DNA and RNA, viruses belonging to different types and families (systems) are shown. A test was conducted using Rus.

H3V2. According to the present invention, SFV, HR3V, HIV and MSv viruses Examples of experiments conducted to determine the activity of some fibroblast growth factors Listed as. The following strains were used in the experiment. A polyploidic strain of human arterial smooth muscle cells (A8 17), aneuploid strain of epithelial carcinoma Hep#2, human primary lymphocyte culture and Pulp C mouse primary fibroblast cultures. The former two strains were used Herpes simplex virus H8v2 type 2 strain and Semlikiforestou virus (SFV). It is stabilized for 24 hours in single tissue/borrowed cells in monolayers and in cell suspensions by tryptic digestion. Titration in a plate with 96 wells and 4 [cell pathology effect end point] It was discovered by observing (CEP).

Strain A617 is intolerant to human respiratory syncytial virus (HRSV). and therefore only Hep#2 cells were used in monolayer and suspension for this infection. It was done. For monolayer experiments, a concentration of the substance being tested is incubated in the culture. and propagated in 96 wells after discarding the substrate.

After incubation for 2 hours at 37°C in 5% CO2, 50-1 [10 plaques Forming unit (PFU) no HS V2, also 5Q ~ 10G +7) 50% feeling A staining unit (ID5o) of SFV or HR3V was added.

Other experiments involve suspending cells with a concentration of a substance in a 96-well plate during testing. process directly.

After incubation for 2 hours at 37°C in 5% CO, infection was induced as above. did.

After incubation for a period of time ranging from 24 to 96 hours depending on the type of virus used. , the degree of CPH of the fresh preparation observed under the opposite microscope (35x magnification) It was determined by calculating the number of Treated media compared to infected controls. The percentage decrease in CPE in the culture was transferred onto semi-logarithmic coordinate paper.

The same cultures were then frozen and the virus content was titrated under different experimental conditions. (+, V, (infusion)].

The frozen material was prepared using a methyl cellulose medium. Standard for quantifying plaques on confluent monolayers of Hep#2 cells grown on layers titrated by one of the techniques.

The 1v titer under various experimental conditions was given as PFU.

The significance of the difference between control and treated cultures was evaluated using the [)aaacN test (JASA).

Special Table Sen4-504581 (5) December 1955, pages 1096-1121).

Activity with HIV virus was determined in human peripheral lymphocytes isolated by gradient centrifugation. Tested in primary culture.

Infection was performed using an HIV standard culture medium, and the infected cultures were incubated for 4 days in the presence of the drug. Incubated.

The results were evaluated as follows. After 3 and 4 days of infection, the P24 core was infected. total amount of virus protein (by ELISA) and synthesized RNA (molecules using nucleic acids) fusion technology) was measured and evaluated in comparison with the control.

Primer of fetal fibroblasts from Valve C mice infected with standard doses of MSV virus. Activity on Moroni sarcoma virus (MSV) was tested in Marie cultures.

The results were compared to the control to compare the transformation foci in the treated cultures. The evaluation was based on the reduction in

The experimental results described above are shown in the attached FIGS. 1-9.

Illustration description Regarding the figure, compound F CE 2184 (compound 1) has 153 to 154 Human bFGF consisting of amino acids is shown. To be precise, human hbFGF (as described above) ) 146 amino acid sequences and points on page 116 (7 shield amino acids shown in i vl) 153 amino acid molecule a) with an N-terminal extension of the amino acid The 146 amino acid sequence of F (described above) and the points on page 6 (indicated by iiN) b) a 154 amino acid molecule with an N-terminal extension of 8 amino acids b) This represents an approximately 50:50 mixture of

The method for preparing this compound is shown in the Examples below.

Compound rH-0925J (compound 2) is a human b Indicates FGF. In other words, the 146 amino acid sequence (described above) of human bFGF but with the amino acid Pr at the N-terminus.

Indicates a compound that does not have

This compound was prepared by the method disclosed in European Patent Application Publication No. 63575. I can do it.

"^me++ham bobbin" (compound 3) is a compound consisting of 146 amino acids. The commercially available recombinant bovine bFGF (manufactured by Amershzm).

"(Ss+yzl) bobbin" (compound 3') is a compound extracted from the pituitary gland line. Sales cow b F G F (manufactured by Se+v!1 company).

Figures A and 1B depict cell suspension of A617 cells (Figure IA) and Hep: For MSV2 (strain 592) virus infection performed in 2 cells (Fig. IB), CPE inhibition ratio of Compound 1 (solid line -■-) and Compound 2 (broken line) (...O...) Indicates the The rate of decrease in CPE is shown on the vertical axis, and bFGF concentration is shown on the horizontal axis.

Figures 2A and 2B are cell suspension lines (dashed lines...O...), and in parallel. , Monolayer of Hep#2 cells (Figure 2A) and Hep#2 cells (Figure 2B) (solid line - low) CPE of compound 1 for MSV2 (strain 592) virus infection performed above. shows the suppression rate.

The percentage of CFE decrease is shown on the vertical axis, and the bFGF concentration is shown on the horizontal axis.

Figures 3A and 3B show that cells are suspended in the cell suspension (dashed line...O...) and in parallel. A monolayer (solid line - low) of A617 cells (Figure 3A) and Hep#2 (Figure 3B) CPH of compound 2 for MSV2 (strain 592) virus infection done above. shows the suppression rate. The vertical and horizontal axes are the same as above.

Figure 4 shows decreased production of MSV2 (strain 592) infected virus in Hep#2 cell culture. Compound 1 (center) compared to the control (left bar), which was rated as low 2 (bar graph on the right) and 2 (bar graph on the right).

The vertical axis shows the virus (in units of 1G'PFU/ml) in the various experimental groups. The index is shown, and the horizontal axis shows the bFGF concentration.

Figure 5. Compounds for HR3V virus infection made in Hep#2 cells. Suppression rate of CPE of 1(-〇-), 2(...O...), 3'(-△-) shows. The percentage decrease in CPH is shown on the vertical axis, and the FGF concentration is shown on the horizontal axis.

Figure 7 shows the virus at 3 days (white) and 4 days (hatched) after infection with the HIV virus. The inhibition rate of compound 1 on the synthesis of protein P24 is plotted on the vertical axis, and bFGF concentration is Degrees are shown on the horizontal axis.

Figure 8 shows the virus at 3 days (white) and 4 days (hatched) after infection with the HIV virus. The vertical axis is the inhibition rate of compound 1 on the synthesis of rus RNA, and the bFGF concentration is Shown on the horizontal axis.

Figure 9 shows transformation lesions induced by MSv (Moloney Sarcoma Virus). The inhibition rate of Compound 1 is shown.

Administration of growth factors (FGFs) according to the invention can be carried out using pharmaceutical compositions containing one or more such factors. The product may be used alone or in pharmaceutically acceptable salts or excipients (e.g. as active substance in the form of a possible carrier and/or diluent and/or binder); It can be done.

Examples of pharmaceutically acceptable salts include pharmaceutically acceptable organic acids (e.g. acetic acid, citric acid). , maleic acid, maricic acid, succinic acid, ascorbic acid, tartaric acid) and pharmaceutically acceptable Even salts with possible inorganic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid) good.

Administration may include, for example, topically as well as parenterally, intravenously, intradermally, orally. I can do it.

A particularly preferred route of administration is, for example, for genetic factor infections caused by H8V2, etc. It is a topical route used to treat and treat respiratory infections caused by HR3V. Ru.

Compositions suitable for topical administration include, for example, creams, pastes, ointments, Lone 5; Supports and pessaries for the treatment of uterine infections; For the treatment of eye infections Eyewash: Can be an aerosol for the treatment of HR9V infection in the respiratory system, especially in newborns.

These formulations can be made by known techniques. For example, creams, pastes, soft The cream, Rosilan, is prepared by mixing the active agent (growth factor) with a conventional oil-based or milky excipient. It can be obtained by

Compositions suitable for intravenous or subcutaneous administration include, for example, sterile aqueous solutions or sterile isotonic saline. It can be a salt aqueous solution.

Parenteral administration consists of the active agent and a pharmaceutically acceptable carrier (e.g., sterile water, olive oil). oil, glycol (such as propylene glycol), and when desired, lidocaine hydrochloride Suspensions or solution compositions containing (appropriate amount of) are suitable.

For oral administration, the active agent is in tablets or capsules coated with a gastric and intestinal fluid-resistant layer. For example, diluents (lactose, dextrose, etc.), lubricants (lica, talc, sugar, etc.) (tearic acid, etc.), binders (starch), non-flocculants (alginic acid and its salts, etc.), etc. In addition, compositions containing excipients used in such cases are suitable.

In general, the pharmaceutical compositions according to the invention are generally used in the art and in the field of galenic preparation. It can be prepared by the method described.

The effective dosage depends on the pathological condition being treated, the type of formulation used, the patient's symptoms, and the treatment. Depends on length of treatment.

For example, for topical administration, creams, pastes, ointments, lotions, uterine pessaries , in the form of supplements or eye washes, the growth factor of the present invention may be present in amounts of 1 micromolar to 1 micromolar. Concentrations within the 1 mmolar range can be used.

Administration of the growth factors of the present invention can be used to prevent the spread of the virus and to treat patients who are already infected. is also useful.

bFGF or aFGF should be administered whenever there is a disorder that requires treatment. are particularly desirable because of their known scar-forming and rutting properties.

The following example describes the preparation of FGF growth factors according to the invention (not intended to limit the invention). (not shown).

Construction of a synthetic NA sequence of bFGF and an expression plasmid containing such a sequence It was carried out by the method of European Patent Application No. 363,675. Its fermentation and purification ・The process was carried out as follows.

(1) Fermentation process Bacterial strains E and C obtained from the Insta-Neito Bastowool collection o11 type B was combined with the human gene encoding bFGF and the tetracycline resistance gene. The cells were transformed with a plasmid containing the gene. This transformed strain was transformed into a recombinant non-glycan It was used to produce cosylated h-bFGF (human bFGF). Master cell of this stock Bank (15 frozen glass bottles) and working cell bank (W, C, B,) (70 raspins stored in liquid nitrogen at -190°C) were prepared. W, One of C and B used the contents of Raspin as an inoculum for the fermentation layer.

The fermentation process was carried out in 7 of 101 fermenters filled with 41 media.

Tetracycline hydrochloride was added to the medium to maintain strain selection conditions.

After 20 hours of growth at 37°C, the final biomass was 42g dry weight/2g/l; The production amount of bFGF was 2500±500/1 (for comparison by gel electrophoresis) (measured).

Pure oxygen-rich conditions were required in the fermentation layer to promote β-bacteria growth. .

(b) Initial purification The resulting cells (microorganisms) were separated from the whole fermentation broth by centrifugation. Conclusion The resulting pellet was resuspended in sodium phosphate buffer containing NaCl. It got cloudy.

To destroy cells efficiently, it is necessary to pass them through a high-pressure homogenizer at least three times. there were. The resulting cell lysate is clarified by centrifugation, and the supernatant is collected in the next process. I met.

(C) Purification The clarified supernatant was transferred to Sepharose (trademark) S Fast Flow (cation exchanger). The product was added to a column of Phosphate Sofa (trademark) where the concentration of NaCl increased. The column was eluted using a large concentration gradient. Furthermore, the product , by elution with N a CA' as above. Purified on a 6B column. Finally, replace the bath sofa with Sephadex (trademark). ) on G25 resin, yielding a large amount of product Tsuk Sofa (Sodium Phosphate-E The product was obtained in DTA).

(d) Column disinfection Sepharose S Fast Flo and Sephadex G2S columns with NaOH solution. Washed and disinfected.

Heparin sepharose with a solution of DH8,5 containing 3M NaCl and a solution of DH5, Washed alternately with solution No. 5.

Thus, bFGF designated as FCE 26184 was obtained. This is approximately 50+5Qil1 compound.

-The amino acid sequence of the 155 amino acid form reported by Abraham et al. 1.1154 amino acid human bFGF, but without a Mct residue at the N-terminus, This 154 amino acid sequence is shown in the attached Figure 1.

Consists of the above 154 amino acid form but does not have an Ala residue in the 1st position 15 3 amino acids human bFGF.

Example 2 Synthesis of the 93-120 fragment of bFGF according to the following formula: H-PHe-P be-Phe-Glu-Arg-Leu-Glu-8er-^1ll-person+n- TB-^5n-Tbr-T7r-^rg-5e r-Arg-Ly+-Tyr- 5e r-5e t-Trp-T7r-Vx 1-Ali-Leu-C7+-^ +g-NH2 Its bonding to the resin was accomplished by the techniques described in U.S. Pat. - Obtained via Val. After coupling to the resin, the amino protecting group is trifed at 0°C. It was removed by treatment with fluoroacetic acid.

After deprotection and subsequent neutralization, the peptide chain was prepared as described in US Pat. No. 3,904,594. It was formed stepwise on the resin according to the procedure shown.

1) bFGF fragment H-Arg-Leu- at positions 97-120 according to the following formula Glu-3et-^to-A+n-T7+-A+n-choh+-TH-^+g-S e+-A+g-L7+-77+-3et-3e+-Trp-TYr-Val-^ 1x-Leu-Ly+-^+g-NH2;2) 100-120th position according to the following formula bFGF fragment H-3e! -^+n-A+n-Ty+-^inzuh+- T7+-T7r-Arg-Set-person+g-L7+-TB-3) 1 according to the following formula Fragment H-Tr at positions 03-120! -^to-Thr-T7+-person B-3 er-^+g-L7s-T7+-3er-3er-Trp-TYr-Vxl-A l+-Leu-C7+-^rg-NH2;4) According to the following formula: 103-146 positions 7 ragment H-T7 t-^5lI-Thr-Ty! -A+g-3+r-^ +g-L7+-Ty+-3et-5e+-Trp-T7+-Vll-Al t- Leu-C7+-At g-Th T-GI F-G l n-Ty +-C7 +-Le u-GI7-Pro-C75| Th　t-G　7-Pro-GI7-Gl　n-Ly　+-A　l　! -1 1e-Lea-Phe-Lea-Pro-Me t-3e Soot| A11-C7+-3et-N)I2; 5) Fragment H-Tyr-^tg-3e at positions 106-115 according to the following formula "-Arg-C7s-T7+-5et-3et-Trp-T7+-Nl2;6) Fragment at positions 106-118 according to the following formula: H-T7 t-At g-3 e T-A t g-C75-Ty +-3e r-3e t-T +p-Ty 　r4g　l-＾1z-Leu| NH2・ 7) Fragment H-77+-A+g-5e at position +06-120 according to the following formula +-^+g-L7s-Tyr-5er-3er-Trp-T7r4al-Alt -Lea-C7+-^rg-NJ; 8) Amidated b FGF fragment at positions 106-125; 9) Amidated bFGF fragment at positions +06-130: 10) Amide bFGF fragment at positions 106-135: 11) Amidated and bFGF fragment at positions 106-140.

12) Amidated bFGF fragment at positions 106-146; 131 Amidated, [[ bFGF fragment at positions 17-110.

Examples of formulations FGF eye drop formulations can be formed from the following ingredients.

22 μg of compound Dextran Sulfate 600μg Water for injection 10ml This solution was lyophilized and regenerated with 10 ml of the appropriate sterile diluent at the time of use. You may.

0 50100200 400 100200400 nMbl”GFl・4 170 gg/ml 17 gg/ml 1.7 H97ml +70 ng/ m1170 νg/rnl 17 μg/ml 1.7 μg/rnl 170 ng/n+1''-1 μm-1 The present invention is directed against viral infections caused by enveloped viruses. This invention relates to fibroblast growth factors useful for the prevention and treatment of. For example, the virus , type 2 herpes plexivirus (H3v2), human respiratory system virus Tiumwilm (HR3V), Semliki forest virus (SFU), acquired Virus (HIV) that causes sexual immunodeficiency syndrome, Moloney Sarcoa (M This is the virus that causes SV.

international search report w--1+-, lyu a-1,. b-e+-, PcT/EP90102231 International Investigation report

Claims (1)

[Claims] 1. Type 1 Herpes Simplex α-type herpesviruses excluding HSV1; β- and γ-type herpesviruses Viruses; orthomyxoviruses or paramyxoviruses; tropical viruses; and Caused by an enveloped virus selected from retroviruses and retroviruses. When formulating drugs for the prevention and treatment of viral infections caused by fibroblasts, How to use follicular growth factors. 2. The virus is an α-type herpes virus and type 2 herpes syndrome. The method according to claim 1, which is HSV virus (HSV2). 3. The virus is an α-type herpesvirus, causing herpes varicella/herpes zoster. The method according to claim 1. 4. The virus is a β- or γ-type herpesvirus, and is a cytomegalovirus. The use according to claim 1. 5. A claim in which the virus is an orthomyxovirus and an influenza virus Usage as described in 1. 6. The virus is a paramyxovirus, human respiratory syncytial virus (HR). SV). 7. The virus is a tropical virus and is found in the Semliki Forest. 2. The method according to claim 1, wherein the virus is a virus (SFV). 8. The use according to claim 1, wherein the virus is a retrovirus and is an HIV virus. Law. 9. The virus is a retrovirus, Moloney Sarcoma. The method according to claim 1, wherein the virus is a ma) virus (MSV). 10. the factor is a base 10. The use according to any one of claims 1 to 9, which is a fibroblast growth factor (bFGF). 11. 11. The use according to claim 10, wherein said factor is human bFGF or an analogue thereof. 12. 11. The use according to claim 10, wherein said factor is bovine bFGF or an analogue thereof. 13. Any of claims 1 to 9, wherein the factor is acidic fibroblast saturation growth factor (aFGF). How to use it as described. 14. 14. The use according to claim 13, wherein said factor is human aFGF or an analogue thereof. 15. Claims 11, 12 or 12, wherein said analogue is an entire fragment of said molecule. is the usage described in 14. 16. caused by an enveloped virus as defined in any of claims 1 to 9. Any one of claims 1 to 15, which is used for the prevention and treatment of viral infections caused by Fibroblast growth factor defined as . 17. Envelope as defined in any of claims 1 to 9 for patients in need. prevention and treatment of viral infections caused by certain viruses. A method of administering to a patient an effective amount of fibroblast growth factor as defined in the preceding section. How to administer.