Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – 25 or more amino acid residues in defined sequence
Reexamination Certificate
1997-08-07
2001-12-18
Low, Christopher S. F. (Department: 1653)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
25 or more amino acid residues in defined sequence
C530S328000, C530S329000, C530S330000, C514S002600, C514S015800, C514S016700, C514S017400
Reexamination Certificate
active
06331610
ABSTRACT:
THE FIELD OF INVENTION
The present invention is directed to the method of preventing and treating AIDS and HIV infection using select peptides derived from the beta subunit of human chorionic gonadotropin (hCG), peptide fragments thereof and pharmaceutically acceptable peptide derivatives thereof having antiretroviral activity.
BACKGROUND OF THE INVENTION
Human immunodeficiency viruses (HIV) of type 1 and 2 are lentiviruses from the family of retroviruses that are believed to cause acquired immunodeficiency syndrome (AIDS). Human T lymphotropic viruses (HTLV) of type 1 and 2 are also human retroviruses and cause adult T cell leukemia, neurodegenerative diseases, and immunodeficiency. Thus, there are several types a of pathogenic human retroviruses and as used herein HIV refers to them generically. The transmission of HIV through sexual contact and during pregnancy accounts for up to 90% of AIDS cases worldwide. This transmission is initiated by the passage of HIV across the mucosal barrier of sexual organs or placenta when exposed to infectious body fluids such as semen, vaginal secretions. or blood. The remaining AIDS cases are due to the transfusion of HIV-contaminated blood, needle sharing among intravenous drug users, accidental exposure to HIV-contaminated body fluids during invasive procedures, and other situations wherein infectious virus can come into direct contact with susceptible human tissues.
Effective compounds with anti-HIV activity that could be used to prevent and/or treat AIDS are still lacking. Although initially the results with certain anti-HIV agents, e.g., azidothymidine (AZT) appeared to be promising, it has become clear that toxicity or undesirable side effects of such agents are incompatible with their antiviral activity when used at an effective pharmaceutical concentration (Bourinbaiar & Fruhstorfer,
Cell Pharmacol AIDS Sci
, 3:163-9, 1996). Similar concerns regarding toxicity have arisen upon use of recently introduced new drugs, such as HIV protease inhibitors. Thus, present methods of preventing and treating AIDS and HIV infection are limited and it is thus obvious that better alternative compounds devoid of toxicity and of undesirable side effects must be sought.
The present inventor has contributed to the discovery of several classes of pharmaceutical compounds which may be useful in inhibiting the replication of HIV and other viral pathogens (Bourinbaiar & Lee-Huang,
Adv. Exp. Med. Biol
. 374:71-89, 1995). Among them are:
Pregnancy steroid hormones, progesterone and estrogen, which were found to inhibit HIV replication in macrophages at doses smaller than can be attained by taking ordinary birth control pills.
Sulphated polysaccharide, dextran sulphate, has been described as an agent suppressing cell-to-cell HIV transmission, associating for the first time the mechanism of this compound with the prevention of cell-mediated viral spread.
The low doses of interferon taken orally as means to treat and prevent AIDS and HIV spread in mucosal environment.
A family of heterocyclic compounds named coumarins as potent anti-HIV drugs acting as protease inhibitors. Various derivatives of coumarins are used mostly as oral anticoagulants, e.g., coumadin or warfarin.
A high molecular weight factor of protein origin has been discovered in cells of placental origin as a possible candidate molecule that may help to support the fertility and prevent HIV infection during pregnancy.
An oral immune modulator of bacterial origin, bestatin, as an agent with anti-HIV activity. Three clinical studies have shown that this molecule is safe and beneficial to AIDS patients.
An antibiotic, gramicidin, was found to display anti-HIV, anti-herpes, and sperm-immobilizing properties which makes this compound an attractive candidate for a topical contraceptive with prophylactic capacity against sexually transmitted diseases of viral and microbial origin.
N-tosyl-L-lysyl-cbloromethylketone (TLCK)—a serine protease inhibitor and HIV antagonist.
The immunomodulating agent, levamisole, previously used as a deworming agent and as a drug for adjuvant therapy of malignant carcinomas. has been reported as an anti-HIV agent.
Two proteins derived from medicinal plants were discovered to have anti-herpes activity.
Several steroid and non-steroidal anti-inflammatory drugs such as dexamethasone, prednisone, acetylsalicylic acid (aspirin), ibuprofen, indoprofen, naproxen, nordihydroguaiaretic acid, indomethacin, etc., were tested for their activity against HIV. Some of these compounds such as prednisone have been found to be effective in delaying the progression to AIDS.
Another protease inhibitor, 4′-acetarmdophenyl 4-guanidinobenzoate, an experimental vaginal contraceptive was identified as an anti-HIV agent with activity corresponding to the levels attainable locally.
Cyclosporin—an immunosuppressor used in transplant patients—was described as having anti-HIV activity.
A new class of antiviral agents selected from histamine type 2 receptor antagonists such as famotidine, ranitidine, cimetidine have been identified, with activity at doses that can be attained by oral administration of a standard clinical dose. Independent clinical trials in HIV+ patients have shown beneficial effect without any adverse side-effects.
It is thus clear that the potential number of compounds that can be used in preventing and treating AIDS is quite large. However, among the many drugs that can be used today as anti-HIV agents the most promising ones are those which are naturally occurring in the human body and as a consequence are less toxic and more effective.
Human chorionic gonadotropin (hCG) is mainly known as a glycoprotein hormone secreted by the placenta and is essential for the maintenance of pregnancy. The alpha chain of hCG heterodimer is identical to alpha subunits of related glycoprotein hormones from the pituitary such as lutropin (LH), follitropin (FSH), and thyrotropin (TSH). Each hormone has a distinct beta subunit which confers receptor-binding specificities. The first 114 amino acids of beta chains of hCG and LH exhibit 86% homology as they differ by only 16 residues. However, the CTP of hCG is unique to this hormone since the beta subunit of LH lacks COOH-terminal extension. Both hormones exert their effect through a shared hCG/LH receptor—G-protein coupled single polypeptide that spans the plasma membrane seven times. As hCG-CTP does not bind to the receptor, it is believed that this portion has no biological or immunogenic activity. Due to the unique nature of the COOH-terminus of beta hCG, synthetic fragments comprising residues 109-145 have been investigated for the last 15 years as a birth control vaccine. A phase II trial of a such vaccine has recently been reported demonstrating the feasibility of this approach.
For reasons that are little understood, tumors of various origins appear to express hCG and hence, this hormone serves as an important diagnostic marker of malignancy. hCG was first proposed as an anti-tumor protein when it was observed that 7,12-dimethylbenz[a]anthracene-inducible breast carcinoma was abolished in pregnant rats or rats treated with hCG. In line with this finding, Lunardi-Iskandar et al., have recently suggested that high doses of hCG and beta hCG may be useful for the treatment of Kaposi's sarcoma by causing apoptosis in neoplastic cells. Clinical trials carried out following this report seem to lend support to this proposal.
It is now increasingly clear that hCG is not unique to pregnancy and may be responsible for a number of unrelated physiological functions. Many microorganisms and some relict invertebrates, such as horseshoe crabs, produce beta hCG-like molecules suggesting that they may play a critical role required for their survival throughout evolution. For example, Saccharomyces cerevisiae yeast appear to secrete a substantial amount of hCG-like substance which translates to the curious fact that all tested commercial beers have been found to contain this hormone. hCG is also produced in non-pregnant humans by a wide rang
Coleman Henry D.
Low Christopher S. F.
Lukton David
Metatron, Inc.
Sudol R. Neil
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