JPH01149730A - Retrovirus proliferation inhibitor - Google Patents

Abstract

PURPOSE:To obtain the title inhibitor which is useful in treatment for retrovirus infection, especially AIDS, with excellent combination of safety and efficacy, by containing monosaccharide or disaccharide derivative as an active ingredient. CONSTITUTION:The inhibitor contains, as an active ingredient, monosaccharide, disaccharide, or their sugar alcohol, deoxy saccharide, aminosaccharide, uronic saccharide, sugar acid, cyclitol, or other analogues, or inorganic or organic acid esters therefrom. These compounds sufficiently inhibits the proliferation of retrovirus with extremely reduced dose and can be used to inhibit the progress or development of retrovirus infections, for treatment and prevention. Since it has low molecular weight, the inhibitor is rapidly absorbed into bodies, smoothly distributes all in organs and tissues including brain to manifest its action promptly and continuously for hours, without change in its chemical structure.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a novel inhibitor of retrovirus proliferation. It provides effective drugs, especially for acquired immunodeficiency syndrome (
Aquired Immunodeficiency S
By disclosing a pharmacotherapeutic agent for AIDS (hereinafter referred to as "AIDS"), the present invention will contribute to the prevention, treatment, and prevention of the progression and onset of such infectious diseases.

Conventional technology and its problems As is well known, AIDS and adult T-cell leukemia (Adult T-cell leukemia)
T-cell Leukemia (hereinafter referred to as rATLJ) is a fatal or extremely malignant disease, and preventing and eradicating this infectious disease is currently the most important issue for humanity to overcome on a global level. .

In addition, these diseases are classified as retrovirus infections, and comparative research using various retroviruses is currently being actively conducted in various fields (progressin med).
ical Virology Volume 32, 174-2
Page 11, S. Karger, published in 1985.
History of Medicine, Volume 142, Pages 613-636; 1
987, etc.). Hereinafter, in order to clarify the technically relevant scope of the present invention, known knowledge regarding common attributes of retroviruses will be described.

The main characteristics common to viruses belonging to the Retroviridae family are that they have an envelope, a single-stranded RNA-type genome, and a reverse transcriptase. This virus has a diameter of 1100n.
It has a spherical shape, and its genome consists of a single-stranded RN with a molecular weight of 3 x 106
It consists of A2 molecules, and these two molecules form a dimer or diploid.

The genome forms a complex with reverse transcriptase and virus particle constituent proteins and is present inside the virus particle together with primer t RNA. This virus is known to proliferate through the following steps: Adsorption to the host cell membrane - Invasion into the cell - Uncoating of the virus - Reversal of viral genome RNA to DNA by reverse transcriptase. Integration of DNA synthesized by copying → reverse transcription into host cell DNA; one transcription, one translation; one generation of child virus. Furthermore,
The Retroviridae family is divided into three subfamilies:
Oncovirinae, Lentivirinae, and Spumavirinae [CIassificationnan]
d Nomenclature of Viruses
(Fourth Report of thc Int.
ernationalComm1ttee on T
axonomyof Viruses), Inte
rvirology, vol. 17, pages 124-128, 1982]. Viruses belonging to the Oncovirinae subfamily, also called RNA tumor viruses, infect mammals including humans, birds, and reptiles and cause tumors, myelopathy, arthritis, and
Causes encephalitis etc. As a virus belonging to this subfamily,
For example, human T-cell leukemia virus (HTLV-
IJ), feline leukemia virus, murine introvert virus, murine Moloney leukemia virus, bovine leukemia virus, avian leukemia virus, avian introvert virus, etc. are known. Viruses belonging to the subfamily Lentiviridae are known as viruses that cause slow viral infections, and cause slow-onset infections in humans, sheep, goats, horses, cattle, etc.

That is, after a viral infection, lymph node swelling, arthritis, pneumonia, meningoencephalitis, encephalopathy, immunodeficiency, etc. develop gradually over several months to several years, and most patients and animals who develop the disease eventually die. . Viruses belonging to this subfamily include, for example, human immunodeficiency virus [hereinafter referred to as rHIVJ; conventionally known as HT
LV-m or LAV (Lymphadenopath
HIV-1 and HIV-2 (Science, Vol. 232, p. 697, 1986);
Two types have been isolated and identified], simian immunodeficiency virus, visna virus for ovine encephalitis, Maedi virus for ovine pulmonary fibrosis, caprine arthritis encephalitis virus, equine infectious anemia virus, and bovine lymph node lesion virus. ing. Viruses belonging to the Spumavirinae subfamily are also called formii viruses, and infections in mammals such as humans, monkeys, cows, and cats have been reported, but there are still no special points to note regarding the pathogenicity of these viruses. unknown. As mentioned above, in the present invention, retrovirus means each virus belonging to the above-mentioned Retroviridae family.

Retroviruses are not only important viruses from the viewpoint of infectious diseases of various animals and zoonotic diseases, but also as materials for elucidating tumors and phylogenetics, and viruses used in genetic engineering. It is an extremely important and useful virus as a sexual vector. Therefore, although a large number of various reports have been made regarding this virus, for the sake of convenience, the current status of typical retroviruses will be explained below from an epidemiological perspective.

AIDS is a disease caused by infection with the AIDS virus, or HIV, and it is already well known around the world that its horror lies mainly in the induction of immunodeficiency and the complications and complications of various diseases caused by it. That's right. Since AIDS was discovered in the United States in 1981, the number of AIDS patients has continued to increase every year, and according to an announcement by the WHO, on September 3, 1987,
As of the 0th, there are already 60,653 people worldwide (W
IIOWeekly Epidemiological
Report, Vol. 62, No. 40, Page 301, October 2, 1987). Moreover, the number of cases worldwide is currently increasing at a rate of approximately 2,500 cases per month, and because there are differences in the accuracy of reports by national authorities to the WHO, there are actually approximately 100,000 cases worldwide. It is estimated that there are approximately 10 million infected people. It is well known that the world is currently surrounded by fear and countermeasures against AIDS.

ATL is a disease discovered in Japan in 1977, and is known to be caused by HTLV-I infection. ATL is clinically classified into acute type, lymphoma type, chronic type, and smoldering type. The horror of this disease is that it suddenly changes from a chronic or smoldering type to an acute type, and once the disease develops, patients suffer from immunodeficiency, similar to AIDS.

Currently, it is estimated that there are approximately one million asymptomatic virus carriers infected with HTLV-I in Japan, and approximately 300 cases occur annually.

Furthermore, HTLV-I is widely distributed not only in Japan but also in the μ world belt region spanning the tropics and subtropics.
It has also been reported that HTLV-I infection can cause myelopathy or miniqopathy, which is accompanied by disorders and abnormalities in walking, urination, sensation, etc., and for this reason, ATL is currently considered to be a serious infectious disease along with AIDS. be.

Among the above RNA tumor viruses that infect animals other than humans, chicken I and rhinosarcoma virus and leukemia virus are
This disease is of great economic importance in the poultry industry because it is highly contagious and affects large numbers of chickens. Further, feline leukemia caused by infection with feline leukemia virus is the most prevalent and damaging disease in domestic cats, and is estimated to have a high incidence and mortality rate worldwide.

In addition to the basic research and epidemiology described above, careful and extensive measures and numerous research and development efforts have already been attempted for the prevention and treatment of such retrovirus infections. These can generally be divided into three categories: public health and medical administrative measures and ideas for strengthening the epidemic prevention system; vaccine development; and drug therapy development. The current situation will be explained below in this order.

Various measures and ideas for public health and medical administration: For example, various measures typified in the case of AIDS include inactivation of the virus itself by heat treatment with blood products, sterilization of syringes, containers, instruments, and supplies; , Prevention of mother-to-child transmission through quarantine,
Measures are being taken or planned to disseminate information on how to prevent sexually transmitted diseases through public relations, and to block infection routes that take into account horizontal and vertical transmission of the virus, such as administrative measures through legislation aimed at preventing AIDS. However, as mentioned above, on a global level, the number of AIDS cases is still increasing rapidly every month, so it is natural that the above measures should be taken in today's world, where there is intense international exchange between countries with different customs and lifestyles. Definite effects cannot be expected with just that. Exceptionally, for chicken sarcoma and leukemia viruses, virus-free chicken populations have been successfully established through quarantine seed selection and brooding in isolators; Although it is experimental, it is not practical because it is geographically limited and requires advanced technology and expensive equipment to establish and maintain it.

Vaccine Development Various attempts have already been made to develop niretrovirus vaccines. For example, feline leukemia vaccine (
JP-A-56-127318 and JP-A-62-151
No. 186); Method for producing retrovirus vaccine using feline leukemia vaccine as an example (Japanese Patent Application Laid-open No. 116523/1982); Method for inducing human RNA-type tumor virus antigen for vaccine (No. 126785/1985), ATL Establishment of MT-2 cell line that produces large quantities of vaccine antigens (Unexamined Japanese Patent Publication No. 5
No. 8-146512), ATL vaccine (Unexamined Japanese Patent Publication No. 1986-
166624); AIDS vaccine (WO851048)
No. 97, JP-A-62-26300, JP-A-62-16
No. 4696, Japanese Patent Application Laid-Open No. 62-244393, and Japanese Patent Application Publication No. 62-500592) are publicly known. However, their safety, efficacy, and homogeneity as vaccines have not been fully confirmed clinically, and they are still far from being put to practical use. In particular, the research and development of AIDS vaccines requires the analysis of antigenic mutations of the virus, countermeasures against them, in vitro experiments, animal experiments, clinical trials, and biohazard countermeasures in vaccine production, etc., which require expensive equipment and competent equipment. Securing human resources, cooperation from the general public in clinical trials, etc.
Surrounded by technical, economic and ethical challenges (WI
IOWeekly Epidcmiological
Report, Volume 62, Pages 93-100, 19
1987; Nature, volume 327, page 458,
1987; ASM News, Volume 53, 484~
Page 489, American Society f
or Microbiology published in 1987).

In other words, the commercialization of an effective and authorized vaccine against retroviral infections, such as AIDS, is unlikely to be achieved for several years.

Development of pharmacotherapeutic agents: As mentioned above, in the current situation where the effects and results of emergency measures related to retroviral infections such as AIDS are uncertain or undetermined, IQ,
It is no wonder that the most hope is placed on drug therapy. For example, in drug therapy for AIDS, azidodeoxythymidine (hereinafter referred to as rAZTJ; West German Published Patent No. 3,608,606), which was developed 23 years ago as an anticancer drug, has been rapidly used and has already been used in countries such as the United States, United Kingdom, France, and Japan. It has been officially approved and general administration to AIDS patients has begun.

However, with the use of AZT, fever, nausea, headache,
loss of appetite, insomnia, myalgia, anemia with decreased hemoglobin,
It has been reported that significant bone marrow suppression (leukopenia, neutropenia, etc.), macrocytosis, and other side effects and toxicity occur with significant differences compared to a placebo (New Eng
land Journal of Medicine,
Volume 317, pages 192-197.

(1987). In addition, the mechanism of action of AZT as an antiretroviral agent is thought to be as follows: During DNA synthesis during the reverse transcription process of virus proliferation mentioned above, normal substrates of reverse transcriptase, such as deoxythymidine AZT competes with phosphate as a pseudo-substrate, and once AZT binds to the DNA strand synthesized by the enzyme,
Further elongation of the DNA strand is prevented (Journa
l ofMedical Chemistry, No. 29
Vol., pp. 1561-1569, 1986). That is,
Since AZT does not prevent the virus from adsorbing to the cell membrane and entering the cell, cell-free infection was suppressed, but cell-to-cell infection where infected cells and uninfected cells form aggregates or tissues is not suppressed. has been pointed out (
Monthly Yakuji, Volume 29, Pages 1391-1395, 19
1987). Therefore, in order to overcome the above-mentioned drawbacks of AZT, various efforts and research have been attempted from the viewpoint of AIDS therapeutic agents and antiretroviral agents. For example, the synergistic effect of the combination of acyclovir and AZT, which is known as a treatment drug for cytomegalic infections and genital herpes, and the effect of a deoxynucleoside derivative with a chemical structure similar to AZT on HIV
It has been reported that inhibition of the proliferation of (Nature.

Volume 325, pages 773-778, 1987; Jo
Urnal of Medical Chemistry
y, Vol. 30, pp. 862-866, 1987).

Furthermore, the current AIDS epidemic has spurred screening and research and development of agents that suppress the proliferation of HIV and retroviruses, and these efforts are being focused on drug therapy for AIDS. These trends can be roughly divided into the following three categories: use of known antivirals, antibiotics, anticancer drugs, etc.; use of known immune-enhancing regulators or immunostimulants; complications, malignant tumors, Other treatments such as opportunistic infections. still,
A review article on this has already been published in various quarters by C.J.
Our own of Medical Chemistry
y, Vol. 29, pp. 1561-1569, 1986; Pharma Medica, Vol. 29, pp. 73-
77 pages, 1987; History of Medicine, Volume 142,
pages 619-622 and 662-669, 19
1987, AIDS research and latest trends (Nippon Lindu, 198
7th year special edition) pages 235-327, Nippon Rinsosha 1987
Published in 2017].

For example, regarding antiviral agents, AZT (manufactured by Wellcome), dideoxynucleoside (manufactured by N.I.C.), dideoxycytidine (manufactured by Roche), and Sumilan (manufactured by Roche) are used.
Bayer), foscarnet (Astra), ribavirin (Yamasa Soy Sauce), ansamycin (Pharmitalia), interferon-α (Biogen), HPA-23 (Pasteur Research New) , A.L.
-723 (manufactured by Weizmann Institute), UFC-A (manufactured by Ueno Pharmaceutical Co., Ltd.), Lambren (manufactured by Ciba Geigy), and the like are known. In addition, regarding immune enhancers, isoprinosine (manufactured by Ewport) and IMREG-1 (manufactured by Imreg)
, 5K818 (manufactured by Sansho Kagaku ■), imthiol (manufactured by Mérieux), levamisole (manufactured by Janssen), thymopentin (manufactured by Cilalag), cimetidine (manufactured by Smith Kline), indomethacin (manufactured by MSD), naltrexiran (manufactured by DuPont) ), azimexone, neurotropin (
Nippon Organ ■), lentinan (Ajinomoto ■), glycyrrhizin (Minophagen ■), interferon-γ
(manufactured by Genetech), interleukin-2 (trial drug ■), interleukin-4 (manufactured by Zenzyme), Thymostimulin (manufactured by Weizmann Institute), Sanjoshin/Aspirin (Joshi Washington University type), γ- Globulin (manufactured by Green Cross ■), Transfer Factor, LC9018 (manufactured by Yakult ■), AL-721
(manufactured by Weizmann Institute), ginseng-to, etc. are known. In addition, other treatments include administration of D-penicillamine (manufactured by Taisho Pharmaceutical Co., Ltd.), Brosobra (manufactured by Imre Co., Ltd.) to remove immune function inhibitors, cyclosporine (manufactured by Sandoz Co., Ltd.), an immunosuppressant, plasma exchange, and plasma filtration. , bone marrow transplants, etc. Furthermore, treatment of ATL with HTLV-I monoclonal antibody (Japanese Patent Application Laid-open No. 146512/1983), anti-T4
AIDS therapeutic agent containing cell antibodies as active ingredients (Unexamined Japanese Patent Publication No. 1983-
143328), an ATL treatment containing the antibiotic neplanocin as an active ingredient (JP-A-61-263919), and an AIDS treatment containing interleukin-2 and steroids such as cyclosporin or imran or prednisolone (JP-A-61-263919). No. 62-185028), an antiretroviral agent containing a sulfate polysaccharide with a molecular weight of 5,000 to 500,000, which is a sulfate ester of a pentose or hexose polymer, as an active ingredient (Japanese Patent Application Laid-open No. 62-215529), for the treatment of immunodeficiency. Molecular weight 200-150 with effective tyrosine and glycine residues
0 polypeptide (Japanese Unexamined Patent Publication No. 62-228023) and the like are known. However, all of the drugs mentioned above in connection with antiviral agents are in the trial stage, and their effectiveness and safety have not yet been sufficiently verified and confirmed. Furthermore, as mentioned above, various drugs and treatments have been clinically tried in relation to immune enhancers and other therapeutic methods, but there are no reports that vermilion shows significant effects.

As is clear from the above, there are still no reliable methods for preventing and treating retroviral infections such as AIDS and ATL. On the other hand, as mentioned above, it is also true that these infectious diseases are rapidly spreading to the extent that they are raising social issues on a global scale. Therefore,
It is inevitable that the emergence of antiretroviral agents that are both safe and effective will bring long-awaited good news to humanity, and their practical application is an urgent issue.

Means for Solving the Problems In order to overcome the problems of the prior art described above, the present inventors have
As a result of intensive research, we have successfully developed a retrovirus proliferation inhibitor that is both safer and more effective than conventional drugs. Surprisingly, derivatives of monosaccharides or disaccharides, such as inositol sulfates, inositol phosphates, etc., have been found to be effective against retroviruses, especially HI
It was discovered that the proliferation of V was sufficiently suppressed. Even more surprisingly, MT, which is commonly used in HIV research,
-4 cell line (Gann Monograph on C
ancerResearch, Volume 28, 219-2
28 pages.

1982; Journal of Virolog
ical Methods.

16, pp. 171-185, 1987), it was discovered that when the derivative coexisted in the culture medium, both cell-free infection and cell-to-cell infection by HIV were inhibited.

That is, MOI (Multiple of I
nfection: Multiplicity of infection) H at approximately 0.001
When the derivative is present in the culture medium of MT-4 cells infected with IV, the proliferation of MT-4 cells is not suppressed, but cluster-forming cells (cell aggregates) and free cells without cluster formation under the culture are suppressed. CPE (Cytopathic Effect
The discovery was made by determining whether cells were alive or dead, and by measuring HIV antigen using a fluorescent antibody method. This suggests that the derivative inhibits both the retrovirus adsorption/invasion process into cells and the reverse transcription process. Furthermore, the following advantages have been found regarding this derivative: The above-mentioned known sulfate polysaccharide (Japanese Unexamined Patent Publication No. 62-215529), which has been used as an antiretroviral agent, has a molecular weight of about 5,000 to several tens of blades. In contrast, the derivatives mentioned above have a molecular weight of less than 1000,000 or less, and are extremely low-molecular substances, so they are not recognized as foreign substances by the body's immune system, and they themselves do not contain antigens. Since it does not exhibit sexual activity, it is unlikely to become an allergen. This means that the retrovirus proliferation inhibitor according to the present invention can sufficiently withstand continuous use under long-term drug therapy without inducing allergies, and
means suitable. Furthermore, the advantage of being a low-molecular substance is that, compared to the above-mentioned high-molecular polysaccharides, it is better and more rapidly absorbed into the body, and is widely and smoothly distributed to various organs and tissues including the brain, and has a lower metabolic rate. Since it has a low probability of being degraded by enzymes and is stable against heat, the derivative can be stored in the body for a long time without denaturing or changing its chemical structure. This means that the efficacy of the retrovirus proliferation inhibitor according to the present invention appears quickly;
Moreover, this means that it extends widely throughout the body and lasts for a long time. Furthermore, although the above derivatives are widely used in the public domain, there have been no reports of their toxicity or harmful effects in toxicity or carcinogenicity tests in various fields. For example, acute toxicity in mice and rats (LD
5o) is 2500 mg/kg or more for subcutaneous inoculation and 5000 mg/kg or more for oral administration (Japanese Patent Application Laid-Open No. 113-1989).
No. 030, JP-A-54-1133443, JP-A-57
-112324); Acute toxicity (LD50) of inositol hexaphosphate (phytic acid) in mice is 500 mg/kg (Toxic 5ubstance) after intravenous inoculation.
es Li5t (1982-1983 edition), N
I OS H (National 1nst1tut
e for Occupational 5afety a
nd Health)], and their acute toxicity is extremely low. Furthermore, it has long been known that the above derivatives exist in large amounts in the animal and plant kingdoms. For example, inositol derivatives are contained in tens to hundreds of mg in 100 g of foods such as grains, beans, citrus fruits, cabbage, green peas, beef heart, raw liver, and brewer's yeast. , widely distributed in the heart, red blood cells, brain, eyes, thyroid, Hanamaru, etc. ("Food Chemistry" Correction No. 7
edition, pages 30 and 123-124, written by Hisataka Iwata, published by Yokendo in 1962). This means that, like well-known nutritional supplements and vitamins that are already in regular use, the retrovirus proliferation inhibitor according to the present invention can be used as an over-the-counter drug for the prevention of retrovirus infection and can be used regularly at home or on a daily basis. This means that it is suitable for taking medication. The present invention
It was completed based on these findings.

That is, according to the present invention, the retrovirus proliferation inhibitor described in the following items 1 to 3 is provided.

■ A retrovirus growth inhibitor characterized by containing a monosaccharide or disaccharide derivative as an active ingredient.

(2) The retrovirus growth inhibitor according to item 1 above, wherein the monosaccharide or disaccharide is a monosaccharide or disaccharide, or its sugar alcohol, deoxy sugar, amino sugar, uronic acid, sugar acid, sulfur sugar, or cyclitol.

(2) The retrovirus proliferation inhibitor according to item 1 or 2 above, wherein the monosaccharide or disaccharide derivative is an inorganic acid ester, organic acid ester or ether of the saccharide.

The retrovirus proliferation inhibitor of the present invention contains a monosaccharide or disaccharide derivative as an active ingredient.

That is, the active ingredient is at least one selected from the group consisting of monosaccharide derivatives and disaccharide derivatives, and usually contains at least a medicinally effective amount of the active ingredient.

Hereinafter, the active ingredients and drugs according to the present invention will be explained in more detail.

(1) Monosaccharides: Monosaccharides in the present invention include the following monosaccharides with a carbon number ranging from 3 to 10 and their isomers, such as glycerose, triose such as dihydroxyacetone, and erythritol. , tetrose such as threose, erythrulose, arabinose, xylose, ribose, lyxose, ribulose, xylulose,
Pentose such as abiose, glucose, galactose, mannose, talose, fructose, sorbose,
Known natural or synthetic hexoses such as tagatose, psicose and streptose, hebutoses such as aldoheptose and sedoheptulose, octose, nonose and decose can be mentioned. In addition, the monosaccharide in the present invention includes various derivatives of the above-mentioned monosaccharides, such as sugar alcohols, deoxy sugars, amino sugars, uronic acids, sugar acids, sulfur sugars, and cyclitol. Specific examples include deoxy sugars such as deoxyribose, deoxyhexose, and dideoxyhexose, amino sugars such as glucosamine, galactosamine, aminouronic acid, sialic acid, and muramic acid, and uronic acids such as glucuronic acid, galacturonic acid, mannuronic acid, and guluronic acid. , sulfur sugars such as thioglucose and thiomethylribose, glycerin, treit, erythritol, arabit, ribit, xylit, sorbitol,
Examples include known natural or synthetic sugar alcohols such as mannitol, idit, talit, dulcit, and alit, and cyclic sugar alcohols such as inositol and quercitol, ie, cyclitol.

In the present invention, among the above monosaccharides, cyclitol,
For example, it is desirable to use inositol.

However, the present invention is not limited to this.

(2) Disaccharide: The disaccharide in the present invention is the same or different two selected from among the monosaccharides having 3 to 10 carbon atoms, their isomers, and their various derivatives as mentioned above as monosaccharides.
It is a combination of two molecules. Specific examples include scroll, maltose, lactose, turanose, cellobiose, trihalose, and the like.

(3) Derivatives of monosaccharides or disaccharides 2 The derivatives serving as active ingredients in the present invention include inorganic acid esters, organic acid esters, ethers, etc. of the saccharides mentioned in (1) and (2) above. For example, phosphoric acid esters which are compounds of the various monosaccharides or disaccharides mentioned above and known inorganic or organic acids;
Examples include sulfate ester, acetate ester, butyrate ester, and the like. Further, methyl or ethyl ethers, which are compounds of the above-mentioned various monosaccharides or disaccharides and methanol, ethanol, etc., can be mentioned. More specifically, the number of molecules of the inorganic acid or organic acid that has an ester bond or ether bond with the above various monosaccharides or disaccharides is about 1 to 20, and in the case of an ester, it usually has an ester bond with the sugar. The acid is used in the form of a salt with one or more cations such as potassium, sodium, calcium, magnesium, barium, aluminum, ammonia, etc.

Preferred specific examples of the above include monosaccharides such as sodium inositol hexaphosphate, potassium inositol hexasulfate, potassium galactose pentasulfate, potassium glucose pentasulfate, potassium zulcit hexasulfate, potassium sorbitol hexasulfate, etc. Examples include derivatives, disaccharide derivatives such as sucrose potassium octasulfate salt, lactose potassium octasulfate salt, and maltose potassium octasulfate salt.

However, the present invention is not limited to these materials.

(4) Mixing or combination of drugs (2) According to the present invention, the above (3)
1 from the group consisting of saccharide derivatives shown in )
By appropriately selecting a species of substance, a drug containing only the substance as an active ingredient is provided.

It is also possible to provide a drug prepared by selecting two or more substances from the above group and then mixing or blending these substances as active ingredients. Furthermore, if additive or synergistic medicinal effects are observed, the substance according to the present invention and
It is possible to provide a drug prepared by blending the known drugs shown in the prior art described above, such as glycyrrhizin and isoprinosine. In addition, when a known drug is mixed, it is desirable to select and mix a known drug whose mechanism of action in the retrovirus propagation process is different from that of the substance according to the present invention.

(5) Amount used or administered: This differs depending on the substance selected from the above derivative group according to the present invention. It also varies depending on the dosage form, number of administrations, age, body weight, severity of symptoms, and purpose of use regarding prevention before infection or prevention of progression to onset after infection.

As a guide, the amount used or administered per day is 1 kg body weight.
It is preferably in the range of about 1 to 1000 mg per g for humans and about 1 to 2000 mg for animals such as livestock.

(6) Dosage Form and Preparation 2 The retrovirus proliferation inhibitor of the present invention may be prepared in any known dosage form, such as powder, tablet, capsule, granule, liquid, syrup, injection, or combination of oil and fat with a surfactant. It can be used as an emulsion, a liposome, an ointment, a preparation adsorbed onto a support such as activated carbon or calcium phosphate gel, a poultice, an aerosol, or a half-open solution. In the production or formulation of each of the above-mentioned dosage forms, commonly used solvents, excipients, and additives can be used depending on the purpose. For example, solvents and excipients include water, physiological saline, alcohol, carbohydrates such as starch and lactose, gelatin, polyvinylpyrrolidone, crystalline cellulose, polyethylene glycol, hydroxypropylcellulose, carboxymethylcellulose, glycerol ester, calcium phosphate, etc.; In addition, additives may be appropriately selected from magnesium stearate, calcium stearate, silicic anhydride, lubricants such as talc, preservatives, sterilizers, wetting agents, emulsifiers, colorants, fragrances, masking flavors, etc. By combining these, formulations can be prepared according to conventional methods.

The retrovirus proliferation inhibitor of the present invention is usually sealed in a vial, ampoule, medicine package seal, etc.
It can be provided in solid dry, syrupy or liquid form. In addition, such inhibitors are used by ingestion, subcutaneous injection, etc., in accordance with the instructions on the dosage and administration label attached to each preparation.

EXAMPLES Hereinafter, specific examples of the present invention will be explained by giving experimental examples and examples. However, the present invention is not limited only to the following experimental examples and examples.

Experimental example 1 Preparation of cell culture medium 2 Commercially available liquid culture medium for cell culture, RP
MI-1640 (manufactured by Flow, UK) with a final concentration of IO
Fetal bovine serum (manufactured by Flow, UK) was added and mixed to give V/V%. The preparation was used as a growth medium as well as a maintenance medium. This is hereinafter referred to as a "medium." In addition, the pH adjustment of the medium is as follows: 7. An appropriate amount of a 5W/V% sodium bicarbonate aqueous solution and carbon dioxide gas were added and mixed. The medium was usually used for cell culture after being adjusted to pH 6 or 8.

Experimental Example 2 Preparation of HIV seed virus solution: TALL-1 cell line (TALL-1 cell line established from T cells derived from the bone marrow of acute leukemia patients)
Nature, Volume 267, Pages 843-844, 1
HIv persistently infected cells, TALL-1 cell (TALL-1/LAV) strain, created by infecting LAv (977) (Abstracts from the 34th Annual Meeting of the Japanese Society of Virology, p. 67, 1)
986) at 37°C in the medium described in Experimental Example 1.
After culturing for days, the cell culture was centrifuged at low speed and the supernatant was diluted with H
It was used as an IV seed virus solution.

Experimental Example 3 Preparation of HIV solution: TALL-1 cell line was cultured in a 200 mQ plastic culture flask at 37°C for 3 days using the medium described in Experimental Example 1, and the number of cells collected by low-speed centrifugation was 1. .5 x 107 cell culture pellets at an infectious dose of 104.5 TCIDs.

/mQ of HIV seed virus solution, mixed thoroughly, and then placed in a carbon dioxide gas incubator (55°C) set at 37°C.
The cells were left to stand for 4 hours in a vacuum (V/V% carbon dioxide/air, humidity 95%) to adsorb HIV to the cells. After the adsorption was completed, unadsorbed HIV was removed by low-speed centrifugation, and the cells were washed. Medium is then added to the washed infected cells to resuspend the cells and bring the volume to 40 mQ. This was transferred to a 2001TIi 2-volume plastic culture flask and incubated in the 37°C carbon dioxide gas incubator for 5 days.
V was cultured.

After completion of the culture, the HIV culture was centrifuged at low speed, and the supernatant was collected and used as an HIV solution for later use.

(Note) TCID5 o: 50% tissue infection (me)
dian tissue culture infection
Experimental Example 4 Cell culture for titer assay of HIV growth inhibitor: Characteristics obtained by mixed culture of leukemic leukocytes isolated from peripheral blood of ATL patients and normal leukocytes isolated from normal human peripheral blood A transformant, the MT-4 cell line (described above), was used. This cell line has a specific glycoprotein T on the surface of helper T cells.
4 antigen (recognized by the commercially available monoclonal antibody rOKT4J) compared to other cell lines.
High susceptibility to IV infection, HTLV- on the cell surface
It is widely used in HIV research because it is known for the expression of I-specific antigen, the appearance of CPE due to HIV infection, etc. (as described above). The medium described in Experimental Example 1 was used for culturing the MT-4 cell line. The cell concentration at the time of implantation was 3X105 cells/
mQ, a 200-capacity plastic culture flask was used as the culture vessel, and culture was performed for 5 days in the 37°C carbon dioxide gas incubator described in Experimental Example 3. The obtained cell culture was
It was subjected to a titer assay of an HIV growth inhibitor.

Example 1 Preparation of retrovirus growth inhibitor 8.0 g of sodium chloride, 0.2 g of potassium chloride, 1.15 g of sodium hydrogen phosphate and 0.2 g of potassium dihydrogen phosphate
Each was weighed out, dissolved in distilled water to obtain IQ, and sterilized under high pressure to prepare a phosphate buffered sodium chloride solution (hereinafter referred to as rPBsJ). Next, 1 g of inositol hexasulfate hexapotassium salt (manufactured by Sigma, USA) was weighed out, dissolved in the above PBS to make 10 m (2), and then transferred to a 50 mG vial and used as a retrovirus growth inhibitor. .

Also, for inositol hexaphosphate 12-sodium salt [manufactured by Sigma, USA], 1 g was weighed out in the same manner as above, and then
Dissolve in PBS to make 10mG, 100mg/mQ
After preparing the PBS solution, it was transferred to a 50m (! volume) vial and used as a retrovirus growth inhibitor.

Example 2 Potency assay of retrovirus growth inhibitor (a)
Preparation of HIV-infected cell suspension: MT-4 obtained in Experimental Example 4
Using cell culture, 5 m of cell suspension (2) with a cell concentration of 4 x 105 cells/- was prepared in a 50 nB2 centrifuge tube.
103TCI D50/mQ of HIV virus solution 0.
5mQ was inoculated and the Mol was approximately 0.001TCIDs o
MT-4 cells were infected with HIV such that After inoculation, mix thoroughly, and the subsequent procedures and conditions are as in Experimental Example 3.
HIV adsorption was performed in the same manner as described. However, the adsorption time was 1 hour. Next, 44 mQ of medium was added and mixed, unadsorbed HIV was removed by low-speed centrifugation, and infected cells were washed. Experimental example 1: Infected cells at the bottom of a centrifuge tube
The cells were suspended by adding the medium described in , and the total volume was reduced to 10
The suspension was made into mQ and used as an HIV-infected cell suspension. At the same time, cell suspension 1 with a cell concentration of 2 x 105 cells/mQ
0rll12 was prepared and used as a control without infection with HIV.

(b) Dilute preparation of retrovirus proliferation inhibitors: Each retrovirus proliferation inhibitor obtained in Example 1 was diluted with the medium described in Experimental Example 1 and adjusted to various concentrations. Regarding the inositol hexasulfate 100 mg/1110 PBS solution, first dilute it 5 times with the above medium to obtain a concentration of 20 m
Four solutions of g/mQ were prepared.

Furthermore, this was diluted stepwise 2 times with a medium, and the concentration per medium was 20000.10000.5000.2.
Inositol hexasulfate solutions of 500, 1250 and 625 were prepared at 2ITII2 concentrations each.

In the same manner as above, inositol hexasinate 100mg
The /mQPBs solution was also diluted 25 times with the above medium, then diluted stepwise by 2 times, and inositol hexaphosphate solutions with concentrations of 4000, 2000, 1000, 500, 250 and 125 μg per drop of the medium were prepared Each concentration 2mf
Two copies were prepared. Each of these diluted preparations was subjected to the following titer assay to determine the effective amount of retrovirus growth inhibitor.

(c) Preparation of sample plate: This was carried out using a 96-well, flat-bottomed plastic microculture plate (manufactured by Corning, Inc., USA) (hereinafter referred to as "plate") consisting of 8 vertical holes and 12 horizontal holes. To prevent dryness and keep the inside moist, first use vertical flutes 1, 6, 7 and 12.
To each person in the row and to each person in rows 1 and 8 of the flutes, pipet 20 ml of PBS using a multichannel pipette (manufactured by Flow, UK).
0 μQ was dispensed, and these holes were not used for the following operations. Next, 100 μQ of the medium prepared in Experimental Example 1 was dispensed into each person's 4 holes in the second horizontal row of the plate at two locations using the pipette described above.

In the same manner as above, 100 μQ of the diluted preparation obtained in (b) above was dispensed into each person at two locations in the four holes in the third horizontal row.

Following the same procedure, 4 wells in 2 rows for each dilution preparation.
A location was assigned, and 100 μQ of the same sample was dispensed into each formula. Next, 100 μQ of the comparative cell suspension obtained in (a) above was dispensed into each of the 2nd to 5th columns using the pipette described above. In addition, 100 μQ of the HIV-infected cell suspension obtained in (a) was dispensed into each formula in the 8th to 11th columns in the same manner as above. Next, the plate was placed in a shaker to thoroughly mix the two, and then used as a sample plate. The sample plate was cultured in a carbon dioxide gas incubator at 37° C. for 5 days in the same manner as described in Experimental Example 3. In addition, two identical sample plates were prepared,
One of them was used as a pilot to observe changes over time during culture. In addition, the remaining one plate was used as a sample for counting the number of living cells and indirect fluorescent antibody method.

(d) Counting the number of living cells 2 In the test plate prepared in (c) above, the proliferation of MT-4 cells, the rapid proliferation of HIV, and the spread of infected cells proceeded simultaneously. In infected cells, CPE such as cell swelling, zincytium formation, multinucleated giant cell formation, obesity, decreased vitality, and death are observed as HIV multiplies. Among the above CPEs, titer assay was performed using the degree of cell death due to HIV infection as an index.

That is, the effect and effective amount of the retrovirus proliferation inhibitor are quantified based on the calculation of living cells under HIV infection. The number of viable cells was counted using the 0.2W ha% trypan blue staining solution prepared by dissolving it in PBS as described in Experimental Example 1 at °C as follows. Add and mix 0.5 mf2 of the cell culture suspension collected from the hole of the specimen plate after completion of the culture described in (c) above to 0.5 tsp of trypan blue staining solution dispensed into a small test tube, and stain the cells. did. Dead cells are stained with trypan blue staining solution, but living cells are not stained, so using this as a criterion, the number of living cells was counted using a hemocytometer using a microscope. The calculation results are shown in Tables 1 and 2. Inositol hexasulfate has a cell survival rate of approximately 100 at a concentration of 2500 μg/mQ in the culture medium.
%, and the proliferation of HIV was almost completely suppressed (Table 1). For inositol hexaphosphate, the concentration in the culture solution is 2.
At 000 μg/mQ, the proliferation of HIV was inhibited by about 90% (Table 2).

Table 1 (Anti-HIV effect of inositol hexasulfate) * 100
X Calculated based on (1)/(2); If the value exceeds 100 due to variation in measured values, set it as (100). Table 2 (Anti-HIV effect of inositol hexaphosphate) Tea 100
Calculated based on X (1)/(2).

(e) Detection of HIV antigen by indirect fluorescent antibody method: HIV
The HIV antigen produced within infected cells can be detected using anti-HIV antibody-positive human serum as a secondary antibody and FI as a secondary antibody.
Detection was performed by indirect fluorescent antibody method using TC (fluorescein isothiocyanate)-labeled anti-human IgG (manufactured by Dako, USA). According to this, infected cells in which HIV is proliferating are detected as HIV antigen positive by indirect fluorescent antibody method. After completing the above culture, 1.0 ml of cell culture suspension was collected from the hole in the sample plate into a small test tube, washed once with 2 mQ of PBS obtained in Experimental Example 1, and then washed with PBS.
Resuspended in IOμQ. Next, the entire amount of the above resuspended cell solution was dropped into one hole of a 12-well slide glass for indirect fluorescent antibody method. Similarly, for the cells of each sample,
It was transferred to a slide glass and a specimen slide was prepared. After air drying, the specimen slides were fixed with cold acetone for 10 minutes. Incidentally, during this period, HIV was completely inactivated. Then, on the fixed cells of each type on the specimen slide, add 1 ml of PBS.
10 μQ of anti-HIV antibody-positive human serum, which is a primary antibody diluted 0 times, was placed on the plate and allowed to react at 37° C. for 30 minutes in a humid box. After the reaction, the cells on the sample slide were washed three times with PBS, and then the secondary antibody, FITC-labeled anti-human IgG (
4 staining units) 10 μQ was placed on the fixed cells of each formula,
After the reaction, washing was performed in the same manner as above. The slides were mounted in coverslips using a buffered glycerin solution (prepared by mixing 1 volume of 0.5M sodium carbonate-sodium bicarbonate buffer (pH 9.5) and 9 volumes of non-fluorescent special grade glycerin). Afterwards, it was examined using a fluorescence microscope (manufactured by Nippon Kogaku Kogyo Co., Ltd.). HIV antigen-positive cells emit fluorescence, so using this as an indicator, count the number of positive cells and the number of negative cells, and based on the HIV antigen positivity rate = 100X number of positive cells / (number of positive cells + number of negative cells), HIV antigen positivity rate was calculated. The results are shown in Tables 3 and 4.

For inositol hexasulfate, the concentration in the culture solution is 2500μ
g/mQ, HIV antigen positivity rate is 0%, H
IV proliferation was almost completely inhibited (Table 3). For inositol hexaphosphate, the concentration in the culture solution is 2000μg/m
In Q, the proliferation of HIV was suppressed by about 90% (Table 4)
.

Table 3 IH8: Inositol hexasulfate Table 4 IHP: Inositol hexaphosphate Example 3 Potency assay of mixed preparation (I) The concentration of inositol hexasulfate in the medium was 800 μg/
Potency assay was performed on a mixed preparation obtained by fixing mQ and adding and mixing various concentrations of inositol hexaphosphate. The procedure and operation were the same as those described in Example 2.

The results are shown in Table 5. The mixture of inositol hexasulfate and inositol hexaphosphate resulted in a synergistic effect in anti-HIV effect.

Table 5 (1) Each final concentration of inositol hexaphosphate (I) IP) added and mixed with inositol hexasulfate (IH3) at a final concentration of 800 μg/mQ in the medium. *Comparison with no drug added. *Contains IH8 with a final rice grain concentration of 800 μg/diluted.

(2) Same as Table 1.

Example 4 Potency test of mixed preparation (II) The concentration of inositol hexaphosphate in the medium was fixed at 250 μg/ynQ, and various concentrations of glycyrrhizin (manufactured by Wako Pure Chemical Industries, Ltd.) were added and mixed. The resulting mixed preparation was tested for potency. Glycyrrhizin is a glycoside of glycyrrhizinic acid, and has long been known as a herbal medicine derived from the herbaceous root. It is widely used to treat gastric ulcers, hepatitis, etc., and is currently being used as an antiretroviral agent. First, Example 1
Add glycyrrhizin to a final concentration of 1 in PBS as described in
000 μg/mQ, and the subsequent titer assay procedure and operation were performed using the same technique as described in Example 2. The results are shown in Table 6. The mixture of inositol hexaphosphate and glycyrrhizin resulted in synergistic action in anti-HIv effect.

Table 6 (1) Each final concentration of glycyrrhizin (GLR) added and mixed with inositol hexaphosphate (IHP) at a final concentration of 250 μg/mQ in the culture medium.

*Comparison with no drug added. ※※Final concentration 250μg/m
Contains Q IHP.

(2) Same as Table 1.

Example 5 Potency test of mixed preparation (I[)
The concentration of inositol hexasulfate in e-medium was 800.
-Ig/mQ was fixed, and a ten-mixture preparation obtained by adding and mixing various concentrations of glycyrrhizin (manufactured by Wako Shosen Yakumi Co., Ltd.) was tested for potency. The procedure and operation of potency test 7 were performed using the same technique as described in Example 2. As a result, similar to the effect of the mixture of inositol hexasulfate and glycyrrhizin shown in Table 6 above, inositol hexasulfate and glycyrrhizin
- Same as Example 4 when mixing with tiruritin.
A synergistic effect was observed in 1.
(Example 6 Preparation (injection) Inositol hexasulfate hexapotassium salt 50 g, chloride] Nanatrim 44 g Potassium chloride 0.2 g, phosphoric acid; -
Sodium hydrogen 1.15g, potassium dihydrogen phosphate 0.
2g and 5mg of ferrous sulfate heptahydrate at 800"1TI
It was dissolved in distilled water to give Q. potassium chloride f
O, Ig and 061g of magnesium chloride hexahydrate 1
(Dissolved in distilled water to give a concentration of 100-100%.Then, each of the 5 aqueous solutions was mixed to make IQ, and the snake was filter-sterilized, 10m12
The solution was dispensed into 5 m (II) volume vials and sealed with rubber caps and aluminum caps to obtain injections. 1 mQ of this t-propellant contained 50 mg 1 of the above inositol hexasulfate.

1 Example 7 Preparation (tablet) Inositol hexasulfate hexapotassium salt 20g 1 Dengun 38
After thoroughly mixing 40 g of g1 lactose and 2 g of calcium stearate, the mixture was put into a tablet machine to form tablets each weighing 500 mg. One tablet obtained contains 100 mg of the above inositol hexasulfate.

(Example 8 Preparation (tablet) Inositol hexaphosphate 2-magnesium 4-kallidium salt (
After sufficiently mixing 10 g of Sigma (USA), 70 g of dry beer yeast, 1 g of ferrous sulfate heptahydrate, and 19 g of starch, tablets weighing 1 g were molded using a tablet machine in a conventional manner. One tablet of this tablet contains 10% of the above inositol hexaphosphate.
Contains 0mg.

Example 9 Preparation (granules) 8 g of inositol hexasulfate hexapotassium salt, 2.5 g of inositol hexaphosphate 12-sodium salt, 1 ferrous sulfate heptahydrate
After fully mixing 39 g of glucose, 40 g of crystalline cellulose, and 10 g of magnesium stearate, granules were obtained by granulating and drying in a conventional manner. 1 g of this granule contains 80 mg of inositol hexasulfate and 25 mg of inositol hexaphosphate, respectively.

Example 10 Test for determining the effectiveness of anti-retroviral growth inhibitors using avian mustard virus
irology, Volume 23, Pages 313-321, 1
964) to SPF (specified-pa
(Thogen-free) Chicken fetal fibroblasts were cultured as a host, and the culture supernatant was used as the 5R-R8V solution. 5R-R8V solution F was adjusted and used so that the amount of viral infection was 107 focus forming units/m12. On the other hand, a 4-week-old Galchin hamster 40
Animals (average weight 52 g) were procured and divided into the following four groups, each group consisting of 10 animals. The first group (untreated control group) is 5R-R
The sample consisted of untreated normal hamsters that were not inoculated with 3V or administered any drugs. Each hamster in the second group (comparison control group) is inoculated subcutaneously on each back with 1 mQ of the above 5R-R8V solution, but no drug is administered. Each hamster in Group 3 (subcutaneous drug inoculation n>) received the above 5R-R on each back.
After subcutaneously inoculating one dose of 8V solution, a 0.5-fold dilution of the injection obtained in Example 6 with PBS was administered every day during the observation period.
Inoculate subcutaneously with a syringe. Each hamster in the fourth group (oral drug administration group) was subcutaneously inoculated on each back with 1 mQ of the above 5R-R8V solution, and then a 25-fold dilution of the injection obtained in Example 6 with distilled water was performed. .5+nQ will be administered orally via catheter daily during the observation period. Each group of hamsters was placed in a separate breeding cage and reared and observed. Every day during the observation period, the weight of each hamster was measured and the presence or absence of interpolation formation at the inoculation site was observed by palpation. Then, 30 days after virus inoculation, 5R-
To measure R8V gs antibody by complement fixation reaction,
In addition to blood sampling, the presence or absence of interpolation by 5R-R8V at the inoculation site of each hamster was determined by autopsy. It is known that antibodies against the gs antigen (a group-specific common antigen derived from the nucleocapsid of R8V) increase in the blood of 5R-R8V interpolated hamsters. Further, the complement fixation reaction was carried out using a commercially available 96-well V-bottom microplate (manufactured by Sanko Junyaku Co., Ltd.) according to a conventional method.

That is, each hamster serum serially diluted 2 times (56°C1
25 μQ of each of the antigen solution purified from the frozen-thawed supernatant of the 5R-R8V cultured cells and guinea pig complement (inactivated by heating for 30 minutes) were dropped into the plate holes in this order, mixed, and then kept at 4°C overnight. It was left standing to react. Next, 25 μQ of sheep sensitized red blood cells were added to each reaction plate and mixed, and after incubation at 37° C. for 60 minutes, the value of the complement fixation reaction was determined by the dilution factor of hamster serum exhibiting 50% hemolysis. The results are shown in Table 7. In the second group (comparison control group), all hamsters showed interpolation, increased gs antibodies, and decreased body weight. In contrast, in both drug-administered groups (groups 3 and 4), no interpolation was observed, and no gs antibodies were detected. In addition, regarding the weight gain of hamsters treated with the drug last winter, no significant difference was observed between Group 1 (untreated control group) (by test; risk rate α = 0.05) Table 7 *The denominator is The total number of hamsters in each group, the numerator is the number of hamsters in which intrusion formation was observed.

Functions and Effects of the Invention (1) The drug of the present invention sufficiently inhibits the proliferation of retroviruses in extremely small amounts, so it can be used in drug therapy aimed at inhibiting, treating, and preventing the progression and onset of retrovirus infections. Therefore, it can be used as an excellent and effective means.

(2) Compared to known polymeric substances such as sulfated polysaccharides, interferons, and interleukins, the saccharide derivatives of the present invention have extremely low molecular weights, so they do not themselves exhibit antigenicity and do not induce allergies. , is well tolerated under long-term drug therapy.

(3) Furthermore, since the drug of the present invention is a low molecule, it has the following advantages over polymer drugs. In other words, the absorption of drugs in the body is excellent and rapid, and the distribution to various organs and tissues including the brain is extremely wide and smooth.In addition, the probability of being degraded by metabolic enzymes is low, and it is resistant to heat. Because it is stable,
It has a long retention time in the body without denaturation or chemical structural changes. In other words, the medicinal effect appears quickly, has a wide range throughout the body, and has a long duration.

(4) There have been no reports of toxicity or harmful effects regarding the drug of the present invention. In addition, the drug or its analogue is widely distributed in the animal and plant kingdoms, and is also contained in large amounts in foods, so it is consumed on a daily basis. Therefore, the drug of the present invention is extremely safe for use in infants, weak constitutions, and critically ill patients, as well as for long-term use.

(5) Since the drugs of the present invention are safe in themselves, their medicinal effects can be improved by mixing or compounding two or more of them without considering the enhancement of side effects or reduction of drug efficacy due to mixing or concomitant use. A synergistic effect can be obtained. It is also possible to combine it with known drugs, and the same synergistic effects as above can be obtained.

(6) In addition, from the viewpoint described in (3) above, in the same way as commonly used nutritional supplements and vitamins, it is used as a general medicine for home use in daily life to prevent retroviral infections such as AIDS and ATL. Suitable for taking medication.

(7) As is clear from the above, the drug of the present invention is a retrovirus proliferation inhibitor that is superior in safety and effectiveness compared to the conventional technology, and can be widely used as a medical and over-the-counter drug. It is something that can be provided.

(that's all)

Claims (3)

[Claims] (1) A retrovirus proliferation inhibitor characterized by containing a monosaccharide or disaccharide derivative as an active ingredient. (2) The monosaccharide or disaccharide is a monosaccharide or disaccharide or its sugar alcohol, deoxy sugar, amino sugar, uronic acid, sugar acid,
The retrovirus proliferation inhibitor according to claim 1, which is a sulfur sugar or cyclitol. (3) The retrovirus proliferation inhibitor according to claim 1 or 2, wherein the monosaccharide or disaccharide derivative is an inorganic acid ester, organic acid ester, or ether of the saccharide.