The human herpesvirus is a typical envelop virus having double-stranded DNA in its nucleocapsid, and is known to cause a variety of affections to an organism infected with it. In this category of human herpesviruses, these viruses are known: herpes simplex viruses type 1 and 2 (HSV1 and 2), varicella-herpes zoster viruses (VZV), cytomegaloviruses (CMV), Epstein-Barr viruses (EBV) and human herpesvirus type 6 (HHV6).
These viruses are characterized in that after a living body is infected with them first in its early childhood, they infect it latently, that is, continue to be alive as long as the living body lives. As the immunity of the organism changes, their affection recurs and is cured repeatedly throughout its life. In this course, some affections caused by the viruses are so grave that their infected living bodies die. Concerning immunosuppression during organ transplantation, the reinfection and reactivation of this virus affect the result of the operation of organ transplantation itself, so the development of an antiviral agent against herpesviruses is urgently needed for such operations.
This virus is also known for its causing a fatal affection or a sequela such as cerebritis to a fetus or newborn child by infection of mother and fetus by way of transplacental infection. More and more details are known of its relation with the manifestation of symptoms of venereal diseases such as genital herpes (herpes simplex virus type 2), epipharynx cancer, Burkitt lymphoma (EB virus), Kaposi sarcoma (CMV) and AIDS (HHV6). Recently in the course of development molecular biology has made a large number of discoveries related to herpesvirus components. Information has been growing in amount on the mechanism and role of glycoprotein specific to these viruses, enzyme activity in them such as thymidine kinase activity, the characteristic mechanism of genome DNA, latent infection, the base sequences related to the canceration of cells and so forth. However, many points remain to be explained in connection with herpesviruses' life cycle seen in the relation among this virus, its infected cell and the immunity of the organism during latent infection and reinfection, being part of the obstacles to developing an inhibitor against the virus.
As understood from the above, this virus is a dangerous one which has very high pathogenicity, and thus a therapeutic agent against it is urgently needed. However, aciclovir is the only remedy now in use. To make matters worse, the application of the remedy is limited, since the possibility cannot be denied that it has a side effect such as teratogenic effect etc. because it is an antagonist to nucleic acid synthesis.
Since olden times, various physiological active substances arising from mushrooms have been known, and some are used today as medicine. For example, Klestin (Yanagawa et al., Cancer and Chemotherapy 11, 2155, 1985), Lentinan (Suga et al., Cancer Research 44, 5162, 1984), Shizofiran are used as antitumor agents. The active principles of these agents are polysaccharides or glycoprotein arising from bacteria, and their effect is thought to be given by a biological response modifier (BRM) stimulating the immune system of a living body. These agents have no directly antiviral effect.
Recently, it has been reported that pllysaccharides having sulfuric acid radicals, for instance dextran sulfuric acid, show antiviral activity against AIDS viruses (Mitsuya et al., Science 240, 646, 1988). Further, Tochikura and his group suggest that the LEM which is hot water extract of cultured Lentinus edodes mycelia (Med. Microboil. Immunol. 177, 235, 1988) has the same kind of activity. However, these have been nothing but infection inhibiting activity shown in vitro in the inhibition of the absorption of viruses to cells or of the fusion of infected cells with normal cells.
The method of producing the LEM is already described in Japanese Patent Application Laid-Open No. 53-10117. Various kinds of activity in vivo shown by the LEM have been disclosed. This material has been in use as pesticide against the infection with tobacco mosaic viruses. It has been reported to have clinical effect against hepatitis. The LEM is known to be made up of a mixture or complex of polysaccharides whose principal constituent is xylose and arabinose, water-soluble lignin and peptide and diverse inorganic substances, so has a long record of use as health food. With regard to origin as well as constitution, it has an entirely different property from that of Klestin, Lentinan and Shizofiran whose active constituents are conventional chemicals such as glucan and glycoproten.
As described earlier, human herpesviruses cause a grave affection, but their remedies are too few and their application is limited. The development of a therapy for affections caused by these viruses and of a therapeutic agent against them is, therefore, a very pressing problem.
Agents in current use against the viruses, aciclovir and BV-araU which is at present being clinically experimented with are analogues of nucleic acid, and target an enzyme existing in a nucleic acid synthesis system specific to the viruses in order to inhibit the nucleic acid synthesis. However, this does not necessarily work without affecting the nucleic acid synthesis system on the side of the living body. They are really chemicals whose side effects cannot be denied. Thus, a safer and more effective medical agent is required today.
The object of the present invention is, therefore, to provide a safe and entirely new therapeutic agent different from conventional antiviral agents against herpesviruses, which is for inhibiting the proliferation of herpesviruses in cells and the reactivation of and the reinfection with these viruses in an organism which has received a latent infection with the viruses.