Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-01-15
2001-08-14
Travers, Russell (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S251000, C514S443000
Reexamination Certificate
active
06274611
ABSTRACT:
TECHNICAL FIELD
The present invention relates to methods and compositions for treating diseases by inhibiting the activity of cellular enzymes. More particularly, the present invention relates to methods and compositions for treating viral infections by inhibiting cellular enzymes such as casein kinase II.
BACKGROUND OF THE INVENTION
One of the greatest challenges to modern medicine is the treatment of viral infections. Though there are therapies that are somewhat effective against viruses, most of the present treatments have multiple adverse side effects. In recent years, the research into treatment of viral diseases has been spurred by the emergence and rapid spread of viruses, particularly retroviruses, and very particularly Human Immunodeficiency Virus (HIV), that causes acquired immunodeficiency syndrome(AIDS).
The retroviridae comprise a large family of viruses, primarily associated with vertebrates, although there have been a few reported sightings in other animals. Both in the wild and in the laboratory, the retroviridae are associated with many diseases, including rapid and long-latency malignancies, wasting disease, neurological disorders and immunodeficiencies, as well as lifelong viremia in the absence of any obvious ill effects. Despite the variety of interactions with the host, all retrovirus isolates are quite similar in virion structure, genome organization, and mode of replication.
Retroviruses are a class of ribonucleic acid (RNA) viruses that replicate by using reverse transcriptase to form a strand of complementary DNA (cDNA) from which a double stranded, proviral DNA is produced. This proviral DNA is then incorporated into the chromosomal DNA of the host cell, thereby making possible viral replication by later translation of the integrated DNA containing the viral genome. Thus, all progeny cells of the originally infected host cell will contain the retroviral DNA. In addition, when multiple copies of the infectious virus are produced, other cells become infected.
Retroviruses cause both malignant and nonmalignant diseases. Expression of the viral genes of some retroviruses may be oncogenic, or may have other pathologic effects that alter normal cell function or produce cell death. The same virus may cause different diseases in different animals. For example, bovine leukemia virus causes B cell lymphoma in cows, T cell lymphoma in sheep, and immunodeficiency disorder similar to AIDS in rabbits and subhuman primates. The first two human retroviruses discovered were human T cell leukemia virus I and II (HTLV-I and II). HTLV-I was found to cause leukemia in humans. The third such human virus to be discovered, HTLV-III, now referred to as HIV, was found to cause cell death after infection of T-lymphocytes, specifically the CD4 subpopulation. HIV has been identified as the causative agent of acquired immune deficiency syndrome (AIDS) and AIDS related complex (ARC).
In addition to the usual viral capsid, retroviruses have an outer membrane of lipid and glycoprotein, similar to the membrane of ordinary cells. Indeed the lipid of the retroviral membrane is derived directly from the membrane of a previously infected host cell, however, glycoproteins inserted into the viral membrane are unique to the virus itself and are coded for by the viral genome. Infection of a host cell by a retrovirus initially relies on the interaction of various receptors on the host cell surface with the glycoprotein membrane envelope of the virus. Subsequently the virus and cell membranes fuse, and the virion contents are released into the host cell cytoplasm.
The host cells predominantly attacked by HIV are the CD4 cells. Infection of human CD4 cells by HIV has been shown to involve binding of the HIV gpl20 surface glycoprotein to a receptor on the surface of the CD4+ cells, the CD4 molecule itself. Recently it has been observed that binding and fusion of HIV to CD4+ cells is also dependent on co-receptor molecules.
While there are many influences controlling the clinical progression from viral infection to disease, a critical factor in AIDS is the continued replication of HIV within target cells and tissues, especially late in the disease process. The balance between infected cells actively replicating HIV and those harboring the provirus in a dormant state, has not been fully elucidated during the clinically asymptomatic period. Therapeutic intervention to alter clinical progression to AIDS, especially during the asymptomatic period, is needed. It is important to control both active HIV replication, and inhibition of viral activation.
A unique aspect of HIV is the part of its life cycle which consists of the multistep transition from an integrated provirus to the production and release of new virions. This transition phase is known as the efferent phase. Agents that have been shown to initiate activation of this phase in vitro include tumor necrosis factor &agr; (TNF-&agr;), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 6 (IL-6), phorbol esters, heat shock, ultraviolet (UV) irradiation, and others.
The numerous individual steps that make up the efferent phase range from early signaling events at the cell membrane to the budding and release of nascent virions. One of the host cell proteins involved in this process is nuclear factor &kgr;B (NF-&kgr;B). NF-&kgr;B is an inducible transcription factor involved in the regulation of numerous genes. This heterodimeric protein is present in the cytosol as an inactive complex with its natural inhibitor, I-&kgr;B. A variety of activating stimuli result in the liberation and activation of NF-&kgr;B from I-&kgr;B. One theory of activation is that the subsequent translocation of NF-&kgr;B to the nucleus and its association with &kgr;B-binding elements in the HIV promotor are involved in HIV transcription.
In most resting cells, NF-&kgr;B is anchored in the cytoplasm by its association with inhibitory molecules known as I&kgr;Ks. This family of ankyrin-containing inhibitors include I&kgr;B&agr;, I&kgr;B&bgr;, I&kgr;B&ggr;, the p105 precursor of p50, and the p100 precursor of p52. The classic NF-&kgr;B complex consists of a heterodimer of p50 (NF-&kgr;B) and p65 (Rel A). These two subunits are members of a family of factors with homology to the c-rel proto-oncogene. In response to a variety of stimuli, combinations of these cytoplasmic c-rel-like factors translocate to the nucleus and transactivate specific target genes.
With the exception of the viral trans-activator Tat, HIV transcription is critically dependent upon host cell transcription machinery and NF-&kgr;B is an important host cell transcriptional protein for HIV activation. Antioxidants and other pharmacologic agents that block HIV promoter-directed gene expression may interfere with the dissociation of pre-formed NF-&kgr;B from its cytoplasmic inhibitor, I-&kgr;B.
Therapeutic Intervention
Although some antiviral treatments are presently available, additional attempts to design drugs for therapy of viral infections, particularly AIDS, are still necessary. Some therapies used to treat viral infectious, in particular HIV infections, are also used as chemotherapy agents.
During all stages of clinical progression to AIDS, HIV expression continues and may contribute to the cumulative destruction of the immune system. Alternative approaches to HIV-1 treatment currently being studied include (1) use of soluble forms of CD4 or co-receptor antagonists; (2) inhibition of glycosylation reactions necessary for attachment of sugar molecules to viral glycoproteins; (3) inhibition of HIV protease, an enzyme necessary to cleave functional proteins from large protein precursors; and (4) immunization of infected persons to boost their protective immunologic response.
Another treatment for AIDS is use of chemotherapeutic agents. Hydroxyurea for example, has been widely used over the last thirty years for the treatment of human malignancies, especially chronic myelogenous leukemia and other myeloproliferative syndromes. Hydroxyurea inhibits deoxynucleotide synthesis and conse
Butera Salvatore T.
Coligan John
Critchfield James W.
Folks Thomas M.
Needle & Rosenberg
The United States of America as represented by the Department of
Travers Russell
LandOfFree
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