Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1994-12-30
1998-02-03
Tsang, Cecilia J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 21, 530395, 530837, 530838, 4241871, 4241881, A61K 3816, A61K 3921, C07K 100
Patent
active
057144621
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to anti-viral agents, especially agents active against HIV-1 and related viruses.
2. Description of the Related Art
It is known that an initial stage of at least one mode of the infection of humans by RNA and DNA viruses involves attachment of the virus to the membrane of a human cell. In the case of HIV-1 and HIV-2, binding is between a cell surface glycoprotein, known as CD4, and a viral envelope protein known as gp120. Thus, CD4 acts as a cell surface receptor for the virus.
After attachment of the virus to the cell membrane the replication cycle of the virus involves a series of steps, one of which appears to be fusion of the viral envelope with the cell membrane. It might be expected that fusion depends solely on binding of gp120 to CD4. However, it is known that if the gene for human CD4 is transfected into CD4 negative HeLa.cells, these cells are then rendered susceptible to productive infection by HIV-1, whereas transfection of the same gene into mouse L-cells causes these cells to bind the virus but does not allow internalisation to occur. Also, experiments with VSV(HIV) pseudotypes have shown that HIV-1 binds to mouse L-cells transfected with human CD4 but is not internalised. Furthermore, it has been reported that CD4 negative cells from a wide range of human tissues can be infected by HIV-1; such infection is not blocked by preincubation of the cells with an anti-CD4 MAb (Leu 3a) or by incubation of the virus with sCD4. These observations cause us to postulate that fusion of the virus envelope with that of a CD4 positive cell requires the involvement of at least one other cell surface receptor, a "fusion receptor".
SUMMARY OF THE INVENTION
The present invention is based on our discovery that at least one such fusion receptor appears to be a cell surface protein having N-terminal homology to an H2 histone.
The invention provides an agent against human immunodeficiency virus (HIV) and/or related viruses comprising CD4 or a CD4-like substance (for example, CD4-IgFc immunoadhesins, CD4 V1-V2 domains, and CD4-derived peptides) and an H2 histone or H2 histone-like protein. The content of CD4 or CD4-like substance may be less than (for example, less than one-half of) the anti-virally effective dose of the CD4 or CD4-like substance alone.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
In therapeutic use, the anti-viral agent of the invention is normally administered parenterally, for example intravenously. However, administration via the peritoneal cavity may be the most effective route in that it results in entry of at least some of the anti-HIV agent directly into the lymphatic system, where viral replication may be extensive.
The invention also provides the use of the agent described above against HIV and/or related viruses, the agent preferably being administered intraperitoneally, especially in a solution containing an osmotic agent which is a glucose polymer mixture, derived from the hydrolysis of starch, which includes at least 50% of glucose polymers of a degree of polymerisation greater than 12, as described in our British patent specification number 2154469A.
Further, the invention provides a pharmaceutical composition containing the agent described above together with an inert carrier or diluent; it also provides the agent of the invention for use in the manufacture of a pharmaceutical composition against HIV and/or related viruses.
The invention additionally provides a method of treatment of a human or animal subject carrying the HIV virus and/or a related virus, comprising administering to the subject a pharmaceutically effective amount of the agent of the invention. The CD4 or CD4-like substance and the H2 histone or H2 histone-like protein may be administered to a subject together or one after the other, in any order, although preferably with the CD4 or CD4-like material being administered before the H2 histone or H2 histone-like protein.
The invention also provides an H2 histone or an H2 histone-like protein,
REFERENCES:
Birnstiel et al, Derwent Abstract No. 92-333029 (DE 4110409, Mar. 29, 1991 or WO 9217210, Oct. 15, 1992).
Birnstiel et al, Derwent Abstract No. 91-369012 (DE 4110410, Mar. 29, 1991 or WO 9117773, Nov. 28, 1991).
Sandstrom et al, Review Articles in Drugs, vol. 34, pp.-373-390, 1987.
Haynes, Science, vol. 260, pp.-1279-1286, 28 May 1993.
Fox, Bio/Technology, vol. 12, p. 128, 12 Feb. 1994.
Brown, The Washington Post, Jun 10, 1993.
Fultz et al, The Journal of Infectious Diseases, vol. 163, pp. 441-447, Mar. 1993.
Green, Scientific American, pp.-99-105, Sep. 1993 issue.
Laurent-Crawford et al, Virology, vol. 185, pp. 829-839, 1991.
Davies Donald Selwyn
Edwards Robert John
Gooderham Nigel John
Shaunak Sunil
ML Laboratories
Mohamed Abdel A.
Tsang Cecilia J.
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