Method of inhibiting large cell formation

Details Method of inhibiting large cell formation Method of inhibiting large cell formation

1990-09-10

1992-11-17

Cashion, Jr., Merrell C.

Drug, bio-affecting and body treating compositions

Lymphokine

530362, 5303871, 530382, 530394, 530410, 530363, A61K 3702

Patent

active

051644860

DESCRIPTION:

BRIEF SUMMARY
FIELD OF INDUSTRIAL APPLICATION

This invention relates to a novel anti-HIV (human immunodeficiency virus) agent.


BACKGROUND OF THE INVENTION

Extensive molecular-biological and biochemical studies have been undertaken on HIV, since the virus, the HIV, has been uncovered as a cause of acquired immunodeficiency syndrome (hereinafter referred to as "AIDS"). These studies have been successful in gradually unveiling the virus itself, as well as the mechanism of the cell infection with the virus. Two routes through which the cells are infected with the virus reported; a route by which HIV released into blood directly combines with the target T-cells and a route in which cells infected with HIV combines with uninfected cells to form a large cells [Weber, J. N. and Rice, R. A. Scientific American (Japanese version), 18, No. 12, 88-95 (1988)]. At the present, however, almost all AIDS patients die because of the lack of an effective AIDS cure. Studies are ongoing all over the world for discovering anti-HIV agents which are effective for the treatment of AIDS patients infected with HIV.
Only 3'-azido-2',3'-dideoxy-thymidine (hereinafter abbreviated as AZT) has been so far sold on the market as an anti-HIV agent [Mitsuya, H. et al. Proc. Natl. Acad. Sci. USA, 82, 7096-7100 (1985)]. AZT, however, remarkably inhibits bone marrow cell growth, as a side effect, and thus is problematic for long-term administration [Richmann, D. D. et al., New Eng. J. Med., 317, 185-191 (1987)].
AZT is a derivative of 2',3'-dideoxynucleoside. Known at the present as an anti-HIV compound having a similar structure is 2',3'-dideoxycytidine. This compound is under investigation at the clinical stage. Pyrymidine nucleoside derivatives (Japanese Patent Laid-open No. 107924/1988 and puryne nucleoside derivatives (Japanese Patent Laid-open No. 107936/1988) are other compounds which are the derivatives of 2',3'-dideoxynucleoside.
Besides the above-mentioned compounds, soluble CD4 and dextran sulfate are considered to be promising anti-HIV agent candidates and clinical tests are ongoing on these compounds. CD4 is a glycoprotein which is abundantly present, especially on the surface of helper T cells, a major target of HIV. Helper T cells are infected with HIV through strong bonding of CD4 with a glycoprotein called gp120 which exists on the surface of HIV particles. If a soluble CD4 is administered to a patient, gp120 is occupied by this extraneous CD4. This prevents the HIV from bonding with the CD4 existing on the surface of helper T cells, thus prohibiting the infection of helper T cells with HIV.
Dextran sulfate has conventionally been used as a blood coagulation inhibitor or as a cholesterol depressor. The compound has drawn much attention since the discovery of the effect to inhibit infection or replication of HIV [Jpn. J. Cancer Res. 78, 1164-1168 (1987)]. Dextran sulfate, however, brings about a side effect of causing liver disorders. In addition, the blood coagulation inhibiting capability possessed by dextran sulfate makes it impossible to administer this compound to hemophiliac AIDS patients.


Means for the Solution of the Problems

The present inventors have carried out extensive studies on the development of a compound useful as an anti-HIV agent. As a result, the inventors have found that if the amino group on the plasma protein-constituting amino acid residue is chemically modified to convert its polarity from positive into negative, the chemically modified plasma protein inhibits HIV-infected cells and HIV-uninfected cells from fusing together and thus from growing into large cells resulting in denaturing or death of the cells, and yet such a chemically modified plasma protein exhibits the least in vivo and in vitro toxicity. That is, the present inventors have found that said chemically modified plasma protein could be used as an excellent anti-HIV agent.


DISCLOSURE OF THE INVENTION

The present invention is to provide an anti-HIV agent comprising as an effective component a protein of which the polarity of the amino group of

REFERENCES:
Jones et al. Biochemistry vol. 9, No. 24, (1970), pp. 4729-4735.
Butler et al. Method Enzy. vol. 5, (1972), pp. 191-199.

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