Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-02-03
2001-02-27
Geist, Gary (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S046000, C514S579000, C514S588000, C536S027140, C536S027600, C536S027800, C536S027810, C536S028200, C560S313000
Reexamination Certificate
active
06194390
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to the field of reverse transcriptase dependent viruses. More specifically, the invention relates to the use of agents which reduce intracellular concentrations of deoxyribonucleosides as a means to inhibit the replication of reverse transcriptase dependent viruses.
BACKGROUND OF THE INVENTION
Viruses are microorganisms that depend, to some degree, on host cell components for their growth and replication. Viral infection and replication in host cells generally results in disease, whether the host is an animal or plant. Human diseases caused by viral infections include the acquired immunodeficiency syndrome (AIDS) and hepatitis. A general discussion of this field is presented in
Fundamental Virology, Second Edition
, (ed. B. N. Fields, D. M. Knipe, R. M. Chanock, M. S. Hirsh, J. L. Melnick, T. P. Monath, and B. Roizman, Raven Press, Ltd., New York, N.Y. 1991).
Retrovirus Replication
Retroviruses comprise a large family of viruses that primarily infect vertebrates. Many diseases, including the induction of some tumors, are associated with retroviral infection (see
Fundamental Virology
, supra, pp. 645-708). All retroviruses, regardless of their clinical manifestations, have related structures and modes of replication.
Retroviruses contain an RNA genome that is replicated through a DNA intermediate. Inside the cell, the viral genome serves as a template for the synthesis of a double-stranded deoxyribonucleic acid (DNA) molecule that subsequently integrates into the genome of the host cell. This integration occasionally results in the induction of a tumor in the infected host organism. Following integration, a complex sequence of events leads to the production of progeny virions which are released from the infected cell.
Early in the retroviral life cycle, the RNA genome is copied into DNA by the virally encoded reverse transcriptase (RT). This enzyme can use both RNA and DNA templates, thereby producing the first strand of DNA (the negative strand) from the infecting RNA genome and a complementary second strand (the positive strand) of DNA using the first DNA strand as a template. To synthesize these DNA strands, the RT utilizes cellular substrates called deoxynucleoside triphosphates (dNTP).
Human retroviruses can be grouped into the leukemia viruses (HTLV type viruses) and the immunodeficiency viruses (HIV type viruses). HTLV infection may lead to one form of leukemia. Acquired immunodeficiency syndrome (AIDS) is caused by a form of HIV, with HIV-1 being more virulent than HIV-2. Both HTLV and HIV infect peripheral blood lymphocytes (PBL).
Other animal retroviruses include feline leukemia virus (FeLV) and lentiviruses. Virulent FeLV infection generally results in fatal aplastic anemia in cats. Lentiviruses cause a variety of neurological and immunological diseases such as visna in sheep and infectious anemia in horses.
HIV Infection
HIV-1 was first identified as the causative agent of AIDS in 1983. The AIDS pandemic is now one of the most serious health problems worldwide. Catastrophic medical and social consequences are likely to extend into the next century. The World Health Organization (WHO) has estimated that between eight and ten million people are currently infected with HIV, and that approximately ten times as many individuals will be affected in the next decade. The large pool of HIV carriers makes the development of effective antiviral treatments a medical priority.
Hepatitis B Infection
Hepatitis B virus (HBV) is one of at least three (A, B and C) viruses that selectively infect liver cells (for a general discussion of HBV see
Fundamental Virology
, supra, pp. 989-1021). HBV infections tend to be persistent with minimal liver damage or with chronic hepatitis that may lead to cirrhosis or liver cancer (hepatocellular carcinoma or HCC). Worldwide, more than 200 million people infected with HBV.
Other Viruses
Several other viruses that infect humans, animals and plants also depend on reverse transcriptase for replication. These include retroviruses such as the leukemia viruses known to exist in several species, including HTLV-1 in humans, as well as reverse transcriptase dependent DNA viruses, such as the cauliflower mosaic virus (a plant virus).
Antiviral Therapies
There is a critical need to develop effective drug treatments to combat RT dependent viruses such as HIV. Such efforts were recently urged in the United Kingdom-Irish-French Concorde Trial conclusions which reported that the nucleoside analog zidovudine (AZT), a mainstay in the treatment of patients infected with HIV-1, failed to improve the survival or disease progression in asymptomatic patients. Other nucleoside analogs like didanosine (ddl) are currently under evaluation. The effects of ddl on disease progression and patient survival endpoints have not been adequately investigated. Non-competitive HIV-1 RT inhibitors and HIV-1 protease inhibitors have also been recently developed. Despite the high efficacy of these compounds, the initial in vitro/in vivo testing has been characterized by the rapid onset of variants of HIV-1 resistant to these drugs (escape mutants). Despite having different antiviral activities and pharmacokinetics properties, the drugs mentioned here all directly target HIV-1 proteins.
Although this latter approach must be continued, we have developed a different antiviral strategy that targets one or more cellular components that are required for the replication of reverse transcriptase dependent viruses.
SUMMARY OF THE INVENTION
The present invention is based on the discovery that drugs which reduce the intracellular concentration of deoxynucleoside phosphates inhibit the replication of reverse transcriptase dependent viruses. Such drugs act either by inhibiting the intracellular synthesis of deoxynucleoside phosphates or by depleting the intracellular pool of deoxynucleoside phosphates. Viruses sensitive to growth inhibition by limiting deoxynucleoside phosphates are retroviruses, including HIV which causes AIDS, hepatitis B virus, cauliflower mosaic virus, and other reverse transcriptase dependent viruses. As one example, hydroxyurea limits synthesis of the intracellular deoxynucleoside phosphates by inhibiting enzymatic activity of ribonucleoside reductase. Other compounds are known that similarly inhibit accumulation of intracellular deoxynucleoside phosphates by this mechanism or by affecting other biosynthetic steps that lead to production of intracellular deoxynucleoside phosphates. Compounds that limit intracellular deoxynucleoside phosphates can be used in conjunction with antiviral nucleoside phosphate analogs, which are themselves therapeutic as competitive inhibitors of native nucleosides, to increase the effectiveness of antiviral treatment. Compounds that deplete intracellular deoxynucleoside phosphates may be used as an alternative to treatment with antiviral nucleoside phosphate analogs, especially when a virus has become refractory to nucleoside analog treatment.
One aspect of the present invention is a method for inhibiting replication of reverse transcriptase dependent virus in animal cells, comprising the step of administering to the cells a compound that depletes the intracellular pool of deoxyribonucleoside phosphate in an amount effective to inhibit replication of the virus. The virus can, for example, be a retrovirus, or a reverse transcriptasedependent DNA virus. The deoxynucleoside phosphate depleting compound in one embodiment is a deoxynucleotide synthesis inhibitor. In another embodiment, the deoxynucleoside phosphate depleting compound is an inhibitor of ribonucleotide reductase. One preferred compound is hydroxyurea.
The invention can be used on cells in vitro or in vivo. In various preferred embodiments, the animal is a mammal or a bird. Preferably, the animal is a human.
In one specific embodiment, the virus is the human immunodeficiency virus (HIV), such as HIV-1 or HIV-2, and the cells are human cells. In another specific embodiment, the virus is hepatitis B and the cells are human ce
Cara Andrea
Gallo Robert C.
Gao Wen-Yi
Lori Franco
Crane L. E.
Geist Gary
Knobbe Martens Olson & Bear LLP
The United States of America as represented by the Department of
LandOfFree
Procedure to block the replication of reverse transcriptase... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Procedure to block the replication of reverse transcriptase..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Procedure to block the replication of reverse transcriptase... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2580844