Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-06-04
2004-10-12
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S122000
Reexamination Certificate
active
06803379
ABSTRACT:
CROSS-REFERENCE TO RELATED APPLICATIONS
STATEMENT REGARDING FEDERALLY
SPONSORED RESEARCH OR DEVELOPMENT
None
BACKGROUND OF THE INVENTION
The invention relates to the treatment of viral, bacterial, parasitic, benign and malignant proliferative diseases, neurodegenerative diseases, inflammatory diseases, immunological diseases, transplanted organ rejection diseases, and diseases produced by intoxication with heavy metals. The invention relates to the use of specific metal chelating agents including, furoic acid, thiophenecarboxylic acid and their derivatives, analogs and structurally related chemicals as pharmacological agents that can be use effectively to disrupt and inactivate specific transition metal ion containing zinc finger structural motifs in metalloproteins and enzymatically active transition metal ion containing sites in metalloproteinases, and other metal containing motifs structural or functional, which in turn, inactivate the pathogenic virus, pathogenic prokaryotic or eukaryotic cells which produces disease conditions. The invention also includes the inactivation of any newly created biological pathogens and their metalloprotein products heretofore not recognized, such as those use in bioterrorism Since radioactive and non-radioactive materials can intoxicate metalloenzyme systems involved in normal physiological functions, the agents of this invention are also intended to be used for decontamination of animals and patients exposed to heavy metals spontaneously or by the use in bioterrorism.
It will be appreciated that hereinafter the use of the following terms: 1) “metalloprotein disrupting agent” encompasses all of the intended functions of the invention and method including antiviral, antiinfective, antiinflammatory, anticancer, and so on; 2) the broad term “antiinfective” is intended to include antiviral, antibacterial, antifungal, antiparasitic activities, as well as actions against any other infective agent or organism whether natural or synthetic; 3) the term “antiinflammatory” is intended to include any inflammatory response; and 4) the term “decontamination of heavy metals” is intended to include any use of these agents in the treatment of stable or radioactive heavy metal poisoning in man or animals. The term “biological response modifier” is intended to encompass any change in the response of a prokaryotic or eukaryotic cell to a second agent after initial treatment with any of the agents of this invention. It will also be appreciated that the term “anti-inflammatory” is intended to include all inflammatory responses of a metazoan organism such as production of stress heat shock proteins, white blood cell infiltrates, swelling, pain, fever and so on. The term “analgesic” refers to a pain reliever agent that functions in inflammatory conditions.
The role of metal ion containing proteins in physiological actions and pathological responses including cancer, inflammation, proliferative diseases and infectious diseases have been intensively study by many researchers. The inventors have studied the important functions of proteins having amino acid sequences which specifically bind transition metal ions. For example, the inventors have determined the role of zinc finger proteins in cancer, proliferative diseases and viral diseases. Moreover, the inventors have determined the role of numerous metalloproteins, such as the role of iron-finger hormone receptor proteins and zinc finger ribosomal proteins in carcinogenesis and aging.
A review of the literature reveals the critical role of metal containing proteins in physiological actions and pathological responses including cancer, inflammation, proliferative, infectious diseases and heavy metal poisoning (Fernandez-Pol, J A, 2001). The inventors have studied the important function of proteins having amino acid sequences which bind metals, particularly transition metal ions. The inventors have determined the important role metalloproteins in proliferative, inflammatory and infectious diseases. In additions, the inventors have determined the role of other metal ion containing protein complexes, such as the role of iron finger proteins in aging and carcinogenesis.
From the evidence reviewed, one can infer that development of a variety of drugs that control or neutralize metalloproteins may lead to a new therapeutic approach directed at controlling and preventing a wide spectrum of viral diseases, bacterial diseases, fungal diseases, cancer and other diseases involving abnormal expression of metalloproteins. Furthermore, the results suggest that these agents may be useful to prevent transmission of viral diseases and prevent the progression of other diseases. This review of the literature not only points out the limits of our understanding of this system, but also indicates the need for the development of new agents to control metalloproteins.
The specific features, objectives, and advantages of the instant invention and its preferred embodiments will become apparent after review and comparison with the prior art as follows. Remarkably, the instant invention provides agents heretofore not recognized, that interact with high specificity with structural metalloproteins and metalloenzymes essential for viral and cellular functions. However, none of these chelators are specific for zinc, in fact, some of them are more specific for iron, and they may have chelated a variety of transition metals (29). Nevertheless, these studies indicate that zinc plays a complex role in a dose and time-dependent manner in apoptosis.
The recent targeting of individuals and groups with the anthrax bacterium (
Bacillus anthracis
) spores is of great concern, particularly because the pulmonary form of this disease is most often fatal. This indicates the need to develop new antibiotics that will rapidly and effectively destroy the
B. anthracis
which proliferates inside lung and lymph node macrophages. This invention contributes new wide-spectrum antibiotics suitable for the destruction of
B. anthracis
inside macrophages which cannot perform their bactericidal functions in the presence of such bacterium.
Although only a limited number of viruses are currently thought to be adequate for biowarfare, such as smallpox or Marburg virus, there is a large number of viruses that can be made suitable and highly dangerous through genetic engineering manipulation or other selection process. There are thousands of animal and human viruses that have the potential to serve that purpose. Those viral agents that have not been recognized previous as credible biowarfare agents pose a present and clear danger, because there is no protection in the form of vaccines for prevention, no credible therapies, and no detection. The potential for destructive pandemic consequences would be far greater than those of the anthrax bacterium and may be similar to that of ancient smallpox pandemics. An opportunity exist to urgently correct and counteract this situation by developing new effective, low toxicity wide-spectrum antiviral agents. This invention contributes new wide-spectrum anti-viral agents suitable for these purposes.
The next sections discuss the background of this invention with special reference to applications to abnormal physiology, infectious diseases, heavy metal toxicity, special applications to enzymes, and metal complexes (Table 1).
ESSENTIAL VIRAL AND CELLULAR ZINC AND IRON CONTAINING METALLOPROTEINS AS TARGETS FOR NOVEL ANTIVIRAL AND ANTICANCER AGENTS
In this section the inventors summarize the experimental data on the role of a selected group of metalloproteins, particularly viral (v) and cellular (c) zinc finger proteins (ZFP) and iron containing proteins which are involved in cell proliferation, neovascularization, apoptosis, and viral infection. Furthermore, this review summarizes the data embracing the hypothesis that disruption of certain metalloproteins by novel pharmacological agents is a key factor in controlling viral and proliferative diseases. The primary goal of this review is to show the potential therapeutic applications of ZFP disru
Fernandez-Pol Jose A.
Fernandez-Pol Sebastian
Cummings Henry W.
Lambkin Deborah C.
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