Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of... – Primate cell – per se
Reexamination Certificate
2000-06-28
2001-11-20
McGarry, Sean (Department: 1635)
Chemistry: molecular biology and microbiology
Animal cell, per se ; composition thereof; process of...
Primate cell, per se
C435S183000, C536S024500
Reexamination Certificate
active
06319711
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to compositions and methods for inhibiting reverse transcription, and, more particularly, to such compositions and methods for creating a nucleoside analog that disrupts the hybridization step during reverse transcription.
2. Description of Related Art
Retroviruses contain RNA rather than DNA as the genetic material. Those such as that believed responsible for acquired immune deficiency syndrome (AIDS), the human immunodeficiency virus (HIV), function by utilizing the enzyme RNA-dependent DNA polymerase, or reverse transcriptase, to create a DNA strand from the viral RNA for directing viral infection and synthesis within a host system.
It is well known in the art to introduce nucleoside analogs into the host that block reverse transcription from manufacturing DNA by presenting faulty substrates to the enzyme that compete with the naturally occurring nucleosides for incorporation into a DNA strand. For example, azidothymidine (AZT; Retrovir, Burroughs Wellcome) is widely used in cases of HIV infection.
A suggestion has also been made to use L-nucleosides as analogs. Weis et al. (U.S. Pat. Nos. 5,559,101 and 5,672,594) disclose the use of L-ribofuranosyl nucleosides as an antiviral composition.
Lin et al. (U.S. Pat. Nos. 5,561,120; 5,627,160; and 5,631,239) teach the use of dideoxynucleoside analogs containing a dideoxy ribofuranosyl moiety having an L-configuration as an anti-retroviral agent, particularly for HBV. The '160 patent additionally discloses the use of 1-(2,3)-dideoxy-&bgr;-L-ribofuranosyl)-5-fluorocytosine as a potent anti-HIV agent.
Chu et al. (U.S. Pat. Nos. 5,565,438; 5,567,688; and 5,587,362) describe L-nucleoside analogs for treatment of HBV or EBV. The sugar moiety illustrated comprises a 5-membered 2′-fluorinated ring.
It is known, however, that at least some of the previously tested antiviral agents have negative side effects such as cytotoxicity and also limited effectiveness owing to inactivation or digestion prior to reaching the target.
SUMMARY OF THE INVENTION
It is therefore an object of the present invention to provide an effective antiretroviral agent.
It is an additional object to provide such an agent that has reduced cytotoxicity over previously known compositions.
It is a further object to provide such an agent whose mode of action facilitates effective dosing.
It is another object to provide a method of inhibiting reverse transcriptase.
It is yet an additional object to provide a method of introducing an antiretroviral agent into a host cell.
It is yet a fisher object to provide a method of targeting a host cell for delivery of an antiretroviral agent.
It is yet another object to provide a method for making an antiretroviral agent.
It is an additional object to provide a method of making a delivery system for an antiretroviral agent.
It is a further object to provide a composition effective in treating cancers.
It is another object to provide a method of treating cancers.
These objects and others are attained by the present invention, compositions and associated methods for inhibiting the action of reverse transcriptase in a system containing retroviral material, such as a cell infected with a retrovirus. The antiretroviral agent in a particular embodiment of the invention comprises a nucleoside
ucleotide analog containing a six-carbon levo hexose sugar, for example, L-rhamnose. Shown below are the structures of L-rhamnose and L-fucose in two dimensions and in the chair configuration (hydrogens are omitted for clarity except in the case of the two-dimensional rhamnose structure).
This particular sugar is not intended to be limiting, however, and other six-carbon levo hexose sugars are also intended to be subsumed herein, such as other hexoses that are able to be synthesized in a levo conformation.
The treatment method comprises delivering the antiretroviral agent to the infected system, wherein the reverse transcription process is inhibited, halting the viral RNA replication and, hence, the infection. The means by which the inhibition occurs is believed to be by steric hindrance, wherein the reverse transcription process is prevented from elongating a complementary DNA strand from a point at which the nucleoside analog is incorporated, although this is not intended as a limitation.
Delivery may be accomplished by conventional methods, such as via oral dosing or injection. Additional delivery methods are also contemplated, including packaging in liposomes and protein targeting.
Similarly, the spread of cancer can be inhibited by introducing a levo hexose into the cancer cell, the incorporation of which into a nucleic acid strand during transcription inhibits the continuation thereof, thus inhibiting cell division.
The features that characterize the invention, both as to organization and method of operation, together with further objects and advantages thereof, will be better understood from the following description used in conjunction with the accompanying drawing. It is to be expressly understood that the drawing is for the purpose of illustration and description and is not intended as a definition of the limits of the invention. These and other objects attained, and advantages offered, by the present invention will become more fully apparent as the description that now follows is read in conjunction with the accompanying drawing.
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Leon M. Lerner, Interconversions of Hexofuranosyl Nucleosides. I. Synthesis of 9-&bgr;-L-Gulofuranosyladenine from 9-&agr;-D-Mannofuranosyladenine,J. Org. Chem., vol. 37, No. 3 (1972), pp. 470-481.
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Rafool Gordon J.
Thompson Daryl L.
Tillman Timothy N.
Allen Dyer Doppelt Milbrath & Gilchrist, P.A.
McGarry Sean
Promelas Research Corporation
Shibuya Mark L.
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