Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-10-13
2003-09-30
Brumback, Brenda (Department: 1642)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S012200, C514S013800, C514S014800, C514S015800, C514S016700, C514S017400
Reexamination Certificate
active
06627610
ABSTRACT:
TECHNICAL FIELD
The invention is directed to inhibiting viral morphogenesis and viral infection. In particular, it concerns effecting such inhibition by inhibiting the prenylation or post prenylation reactions of a viral protein.
BACKGROUND ART
It has been shown that certain membrane-associated proteins require the addition of lipophilic residues in order to function properly. One family of such modifications is termed “prenylation” because the hydrophobic residue is derived from isoprenoid precursors. The prenyl residue is known to attach to the sulfhydryl group of a cysteine which has been shown in a number of membrane-associated proteins to be contained in a “CXXX” (SEQ ID NO: 1) box at the carboxy terminus of the substrate protein. In particular, one such membrane-associated protein has been shown to be the protein product of the ras oncogene. Summaries of these reactions conferring hydrophobic properties on membrane proteins, including prenylation, have appeared by Hoffman, M.,
Science
(1991) 254:650-651, and by Gibbs, J. B.,
Cell
(1991) 65:1-4.
In addition, in many cases, prenylation is a first step in a series of further reactions which modify the carboxy terminus of prenylated proteins. These prenylation initiated, or post-prenylation reactions include carboxymethylation and proteolysis.
In the prenylation substrate proteins studied to date, the CXXX (SEQ ID NO: 1) box contains aliphatic residues in the second and third positions and a leucine, serine, methionine, cysteine or alanine in the terminal position. Thus, in the CXXX (SEQ ID NO: 1) boxes so far studied, the box itself is relatively hydrophobic.
It has now been found that prenylation of a viral protein is necessary for the morphogenesis of hepatitis delta virus (HDV). This is the first demonstration that viral proteins are subject to prenylation. Furthermore, certain functional consequences can be ascribed to prenylation. The viral protein which is the target of prenylation, surprisingly, contains a hydrophilic CXXX (SEQ ID NO: 1) box of the sequence Cys-Arg-Pro-Gln (SEQ ID NO: 2). Prenylation, or prenylation-initiated modification, of this relatively hydrophilic CXXX (SEQ ID NO: 1) box and corresponding CXXX (SEQ ID NO: 1) boxes (hydrophilic or otherwise) or other cysteine-containing sequences near the C-terminus of proteins in other virions are suitable targets for antiviral strategies.
These targets can now be seen to include, but are not limited to, proteins of hepatitis A virus (HAV), hepatitis C virus (HCV), herpes simplex virus (HSV), cytomegalovirus (CMV), varicella-zoster virus (VZV), influenza virus, plant viruses such as tobacco mosaic satellite virus (TMSV) and barley stripe mosaic virus (BSMV), the core antigen of hepatitis B virus (HBV) and the nef gene product of human immunodeficiency virus-1 (HIV-1)—especially since nef has been shown to play an important role in the development of AIDS. (Kesstler, H. W. III, et al.
Cell
(1991) 65:651-662. Accordingly, inhibition of the prenylation of these target proteins or the post-prenylation reactions thereof is claimed to be inhibitory to the progress of these infections.
DISCLOSURE OF THE INVENTION
The invention provides methods to interfere with viral morphogenesis, production, release or uncoating both in vitro and in vivo. Agents which interfere with the prenylation of, or the post-prenylation reactions of, at least one viral protein are provided to infected cells to halt the viral infection. Such cells may be in culture or may be contained in an animal or plant subject.
Thus, in one aspect, the invention is directed to a method to inhibit viral morphogenesis, production, release or uncoating which method comprises effectively interfering with the prenylation of, or the post-prenylation reactions of, at least one viral protein. In another aspect, the invention is directed to an assay method for screening candidate drugs for their ability to inhibit prenylation. In a third aspect, the invention is directed to a method for treating viral infection by administering an agent effective to inhibit prenylation of, or the post-prenylation reactions of, a viral protein. In preferred embodiments, the viral protein is the large delta antigen of the hepatitis D virus, core antigen of HBV, or the nef protein of HIV.
REFERENCES:
patent: H1345 (1994-08-01), Biller
patent: 5503973 (1996-04-01), Glenn
patent: WO 94/23041 (1994-10-01), None
Benet et al., “Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, and Elimination”, pp. 3-32 in The Pharmacological Basis of Therapeutics, Eighth Ed., McGraw-Hill, Inc., New York, 1990.*
Rice et al., “Discovery and in Vitro Development of AIDS Antiviral Drugs as Biopharmaceuticals”, Advances in Pharmacology 33:389-438, 1995.*
American Heritage College Dictionary (3rd. Ed.) Houghton Mifflin Company, Boston and New York, p. 866.
Beck et al., “Incorporation of a Product of Mevalonic Acid Metabolism into Proteins of Chinese Hamster Ovary Cell Nuclei,”Journal of Cell Biology(1988) 107:1307-1316.
Bruss et al., “Mutation Analysis of Hepatitis B Surface Antigen Particle Assembly and Secretion,”J. Virol(1991) 65(7):3813-3820.
Bukhtiyarov et al., “Photoreactive Analogues of Prenyl Diphosphates as Inhibitors and Probes of Human Protein Farnesyltransferase and Geranyltransferase Type I,”J Biol Chem(1995) 270(32):19035-19040.
Derwent Pub. Ltd., London.: Database WPI; Sec. Ch, Week 9430 (Feb. 1, 1996).
Detroy et al., “Patulin Inhibition of Mycovirus Replication inPenicilluim stoloniferum,” J Gen Micro(1975) 92:167-174.
Finegold et al., “Common Modifications of Trimeric G Proteins and Ras Protein: Involvement of Polyisoprenylation,”Science(1990) 249:165-169.
Gibbs, “Ras C-Terminal Processing Enzymes-New Drug Targets?”Cell(1991) 65:1-4.
Glenn et al., “trans-Dominant Inhibition of Human Hepatitis Delta Virus Genome Replication,”J Virol(1991) 65(5): 2357-2361.
Glenn et al., “Use of Prenylation Inhibitor as a Novel Antiviral Agent,”J Virol(1998) 72(11):9303-9306.
Glenn et al., “Identification of a Prenylation Site in Delta Virus Large Antigen,”Science(1992) 256:1331-1333.
Glomset et al., “Prenyl Proteins in Eukaryotic Cells: a New Type of Membrane Anchor,”TIBSReviews (1990) 15:139-142.
Hancock et al., “All ras Proteins are Polyisoprenylated but Only Some are Palmitoylated,”Cell(1989) 57:1167-1177.
Hoffman, “Playing Tag With Membrane Proteins,”Science(1991) 254:650-651.
Hruby et al., “Lipid Modification of Vaccinia Virus Proteins,” Abstracts of the American Society for Microbiology, 92nd General Meeting, p. 400 (May 1992).
Kaminchik et al., “Genetic Characterization of Human Immunodeficiency Virus Type 1 Nef Gene Products Translated In Vitro and Expressed in Mammalian Cells,”J Virology(1995) 65(2):583-588.
Kestler et al., “Importance of the nef Gene for Maintenance of High Virus Loads and for Development of AIDS,”Cell(1991) 65:651-662.
Kitamura et al., “Primary Structure, Gene Organization and Polypeptide Expression of Poliovirus RNA,”Nature(1981) 291: 547-553.
Kohl et al., “Selective Inhibition of Ras-Dependent Transformation by a Farnesyltransferase Inhibitor,”Science(1993) 260:1934-1937.
Koff, “Prenylation of the Large Hepatitis Delta Virus Antigen: A Target for Antiviral Therapy,”Gastroenterology(1992) 103:1978-1986.
Maltese, “Posttranslational Modification of Proteins by Isoprenoids in Mammalian Cells,”FASEB Journal(1990) 4:3319-3328.
Miura et al., “Inhibition of Protein Prenylation by Patulin,”FEBS Letters(1993) 318:88-90.
Moores et al., “Sequence Dependence of Protein Isoprenylation,”J Biol Chem(1991) 266(22):14603-14610.
Overmeyer et al., “Isopernoid Requirement for Intracellular Transport and Processing of Murine Leukemia Virus Envelope Protein,”J Biol Chem(1992) 267(31):22686-22692.
Oxford Dictionary of Biochemistry and Molecular Biology (Oxford University Press, Oxford (1997)) p. 440.
Pompliano et al., “Steady-State Kinetic Mechanism of Ras Farnesyl: Protein Transferase,”Biochemistry(1992) 31:3800-3807.
Poradosu et al., “Alpha-Cyanocinnamide Derivatives: a New Family of Non-Peptide, Non-Sulfhydryl Inhibitors of
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