Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1998-04-30
2001-06-26
Moezie, F. T. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C562S557000
Reexamination Certificate
active
06251868
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a method for preventing or treating a human immunodeficiency virus (HIV) infection, comprising administering to a mammal in need thereof a HIV infection preventing or treating effective amount of a &ggr;-L-glutamyl-L-cysteine ester compound or an oxidized dimer obtained by dehydrogenation of two identical molecules of such.
BACKGROUND ART
The potential inhibitory effects of anti-oxidative agents, including glutathione (GSH) and its precursors, against human immunodeficiency virus type I (HIV-1), have been investigated over the last several years. In early studies, reducing compounds such as D-penicillamine, 2,3 dimercapto-1-propanol and N-acetylcysteine (NAC) were found to inhibit HIV-1 long terminal repeat (LTR)-directed viral gene transcription (FEBS Letters 1988; 236: 282-286, AIDS Res Human Retroviruses 1990; 7: 919-927, Proc Nati Acad Sci USA 1990; 87: 48844888, Proc Natl Acad Sci USA 1991; 88: 986-990). In parallel with these initial basic studies, reduction of GSH levels in plasma, peripheral blood cells, and lung epitheliallining fluid has been reported in HIV-1-infected-individuals (Biol Chem Hoppe-Seyler 1989; 370: 101-108, AIDS Res Human Retroviruses 1992; 2: 305-311, Lancet 1989; 11: 1294-1298). GSH is known not only as a major intracellular anti-oxidant, but also as an modulator of the immune system (J Immunol 1985; 135: 2740-2747). Hence, altering the GSH deficiency of HIV1-infected individuals by glutathione precursors has been hypothesized to be one of the rational therapeutic strategies to prevent HIV-1 propagation in vivo (AIDS Res Human Retroviruses 1992; 8: 209-215, Blood 1995; 86: 258-267, Blood 1996; 87: 4746-4753). In this manner, the inhibitory effects of GSH pro-drugs, such as NAC, against HIV-1 have been further characterized. These compounds have been shown to be capable of inhibiting HIV-1 gene transcription, which is induced by tumor necrosis factor alpha (TNF-&agr;) or phorbol 12-myristate 13-acetate (PMA), from latent proviruses. This is a model for the cellular latent stage of HIV-1 infection (Proc Natl Acad Sci USA 1991; 88: 986-990, Cell 1990; 61: 1271-1276). Of note, in a recent report, enhancement of HIV-1 growth by NAC was described in peripheral blood mononuclear cells (PBMC) (AIDS 1997; 11: 33-41).
Recent studies have demonstrated that the replication of HIV-
I is continuously active in lymphoreticular tissues (Nature 1993; 362:355-358, Nature 1993; 312: 359-362). Therefore; it may be difficult to significantly alter HIV-1 infection only by keeping latent HIV-1 proviruses in a non-replicative state, without shutting off the massive virus production from so-called late-phase infected cells and subsequent further rounds of infection. It has been implied that, in order to slow down the progression of the acquired immune deficiency syndrome (AIDS), removal of the late-phase infected cells may be critical (Science 1996; 272: 1962). However, there has been no compounds which display a selective removal of HIV-1 itself and HIV-1-infected cells, although a vast number of anti-HIV-1 chemotherapeutic candidates have been described. Similarly, although there have been a various reports which described the anti-HIV-1 effects of a variety of anti-oxidants (FEBS Letters 1988; 236: 282-286, AIDS Res Human Retroviruses 1990; 7: 919-927, Proc Natl Acad Sci USA 1990; 87: 4884-4888, Proc Natl Acad Sci USA 1991; 88: 986-990), no such compound was reported to block acute HIV-1 infection.
The &ggr;-L-glutamyl-L-cysteine ester compound of formula (I):
wherein R is a straight chain, branched or cyclic hydrocarbon group having 1-10 carbon atoms, or a straight chain or branched hydrocarbon group having 1-5 carbon atoms substituted with an aromatic group; or the oxidized dimer obtained by dehydrogenation between two &ggr;-L-glutamyl-L-cysteine esters having formula (I), is known as an anti-oxidant, working either directly or as a unique GSH pro-drug, thereby performing preventive or therapeutic effects against liver disease, cataracts, kidney disease, heart and liver reperfusion injury, arrhythmia, and lung disease, such as asthma, caused by active oxygen and free radical injury (WO 88/00182 (→U.S. Pat. No. 4,927,808) and WO 92/18420 (→U.S. Pat. No. 5,631,234)). In particular, &ggr;-L-glutamyl-L-cysteine ethyl ester (&ggr;GCE) has been reported to be effective against cataracts (Ophthalmic Res 1991; 23: 51-58), hepatic injury (Res Corn Chem Pathol Pharmacol 1993; 82: 49-64), heart and liver reperfusion injury (Brit J Pharmacol 1991; 104: 805-810, J Am Coll Cardiol 1994; 24: 1391-1397, Circulation Res 1994; 74: 806-816, and, Transplantation 1992:54: 414-418) and asthma (Am Rev Respir Dis 1992; 145: 561-565). Howvever, there is not a report on the effects of &ggr;-L-glutamyl-L-cysteine ester compound against HIV infection.
DISCLOSURE OF THE INVENTION
The inventors of the present invention have examined the anti-HIV-1 effects of &ggr;-GCE which represents the above-mentioned &ggr;-L-glutamyl-L-cysteine ester compound in vitro, by using (1) a vigorously HIV-1-producing human T-lymphocytic cell-line, a model for a HIV-1 production from late-phase infected cells in chronic HIV infection and (2) a HIV-1-inoculated T-lymphocytic cells, a model for an acute HIV-1 infection, and have found (1) that &ggr;-GCE displays a novel biphasic repressive effect on chronic HIV-1 infection, unlike other glutathione pro-drugs, or other reported anti-oxidants; that is, i) in high doses, up to a concentration of 2.5 mM, in which neither GSH nor other GSH precursors show inhibitory effects, &ggr;-GCE potently inhibits the production of HIV-1 by a selective cytopathic effect against infected cells, while the viability and growth of uninfected cells are unaffected at the same concentrations, ii) at lower concentrations (200-400 &mgr;M), &ggr;-GCE significantly represses the viral production from chronically HIV1-expressing cells without affecting their viability, and iii) the discrepancy of the thresholds of the toxic doses between infected and uninfected cells is more than ten-fold; and (2) that relatively high doses of &ggr;-GCE, utilized in acute HIV-1 infection of T-lymphocytic cells, entirely blocked the propagation of HIV-1, and rescued the cells from HIV-1-induced cell death, and that &ggr;-GCE at such concentrations was found to directly inhibit the infectivity of HIV-1 within four hours. Those findings indicate that &ggr;-GCE possesses excellent properties as an anti-HIV agent; namely, it is capable of shutting-off all three critical factors in HIV propagation: it inactivates HIV-1 itself, blocks acute infection, represses virus production from infected cells, and kills HIV-1-producing cells selectively, which no other anti-HIV-1 chemotherapeutic agents have ever been attained.
Thus, based on the above-mentioned findings, the present invention relates to a method for preventing or treating a HIV infection, including a new or an asymptomatic infection as well as AIDS, comprising administering to a mammal in need thereof a HIV infection preventing or treating effective amount of a &ggr;-L-glutamyl-L-cysteine ester compound of formula (I):
wherein R is a straight chain, branched or cyclic hydrocarbon group having 1-10 carbon atoms, or a straight chain or branched hydrocarbon group having 1-5 carbon atoms substituted with an aromatic group; or the oxidized dimer obtained by dehydrogenation between two &ggr;-L-glutamyl-L-cysteine esters having formula (I).
REFERENCES:
patent: 4927808 (1990-05-01), Kitahara
patent: 5464825 (1995-11-01), Anderson
patent: 5596011 (1997-01-01), Repiue
patent: 5607974 (1997-03-01), Droge
patent: 5624955 (1997-04-01), Nagasawa
patent: 5824664 (1998-10-01), Schein
patent: 5843785 (1998-12-01), Merzenberg
patent: 276317 (1988-08-01), None
patent: WO 92/21368 (1997-06-01), None
patent: WO 97/21443 (1997-06-01), None
Derwent Abstract of EP 736770A, 1996.
Kitahara Shigehisa
Kubota Satoshi
Pomerantz Roger J.
Lukton David
Moezie F. T.
Sughrue Mion Zinn Macpeak & Seas, PLLC
Teijin Limited
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