Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Virus or component thereof
Reexamination Certificate
1997-04-15
2004-03-30
Scheiner, Laurie (Department: 1648)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Virus or component thereof
C530S324000
Reexamination Certificate
active
06713069
ABSTRACT:
This invention pertains to compositions and methods for detecting, preventing, and treating African Hemorrhagic Fever (AHF). More specifically, the invention pertains to detecting, preventing, and treating infection by the viral agent that causes African Hemorrhagic Fever with the use of antigenic or inhibitory peptides.
Viruses
Many different viruses cause disease in humans and other animals. Viral infections are responsible for many epidemics, including influenza, herpes, and AIDS. Efforts to prevent or cure viral diseases have been hampered by the unusual structures and functions of viruses, which are quite unlike those of other infectious agents such as bacteria, fungi, and protozoa.
A virus consists essentially of a nucleic acid genome surrounded by a lipid-protein envelope. A virus multiplies by invading a host cell and causing the cell to synthesize and package viral components under the control of the viral nucleic acid. Viruses frequently mimic normal cellular mechanisms, making it difficult to synthesize drugs that are selectively toxic to viruses.
The viral envelope, formed from proteins and glycoproteins, is critical to the successful entry of a virus into a host cell. A common pattern exists in the attachment or adsorption of viral particles onto host cell membranes for several “families” of viruses, including the filoviruses, paramyxoviruses, influenza viruses, and retroviruses. An “attachment” or “receptor-binding” viral glycoprotein binds to a specific receptor on the host cell surface. Following attachment of the virus, fusion of the target cell membrane with the viral envelope is promoted by a viral fusion glycoprotein, which probably penetrates the host cell at a particular site and then contracts, drawing the two entities closer together. Following fusion, the contents of the virus merge with the cytoplasm of the cell, and the viral nucleic acid then redirects the cell machinery to effect its own multiplication.
The viral invasion mechanism can potentially be disrupted at any of several points to prevent the virus from gaining access to the inside of a cell. One such means is to block the receptor sites of the viral fusion glycoprotein, or otherwise to prevent the viral fusion glycoprotein or its receptor site from carrying out the attachment or fusion. Such blocking has been achieved for paramyxoviruses with oligopeptides mimicking the binding function of a paramyxovirus viral fusion peptide. See C. Richardson et al., “Specific Inhibition of Paramyxovirus and Myxovirus Replication by Oligopeptides with Amino Acid Sequences similar to Those at the N-Termini of the F
1
or HA
2
Viral Polypeptides,” Virology vol. 105, pp. 205-222 (1980).
Peptides containing the sequence Phe-X-Gly (or analogs) are known to inhibit HIV-1. See U.S. Pat. No. 4,880,779; and W. Gallaher et al., “Membrane Interactions of Human Immunodeficiency Virus,” pp. 113-142 in R. Aloia et al. (eds.),
Membrane Interactions of HIV
(1992); the latter of which also discusses the structure of the HIV-1 gp41 TM protein.
C. Wild et al., “A Synthetic Peptide Inhibitor of Human Immunodeficiency Virus Replication: Correlation Between Solution Structure and Viral Inhibition,” Proc. Natl. Acad. Sci. USA, vol. 89, pp. 10537-10541 (1992); and C. Wild et al., “A Synthetic Peptide from HIV-1 gp41 is a Potent Inhibitor of Virus-Mediated Cell-Cell Fusion,”
AIDS Res. Human Retroviruses
, vol. 9, pp. 1051-1053 (1993) described peptide analogues of the HIV-1 fusion peptide that also inhibit HIV-1. These peptide analogs interfere with the normal function of the fusion protein, thereby preventing fusion and subsequent infection of the cell by the virus. See also C. Wild et al., “The Inhibitory Activity of an HIV Type 1 Peptide Correlates with Its Ability to Interact with a Leucine Zipper Structure,”
AIDS Res. Human Retroviruses
, vol. 11, pp. 323-325 (1995); and C. Wild et al., “Peptides Corresponding to a Predictive &agr;-Helical Domain of Human Immunodeficiency Virus Type 1 gp41 Are Potent Inhibitors of Virus Infection,”
Proc. Natl. Acad. Sci. USA
, vol. 91, pp. 9770-9774 (1994).
S. Jiang et al., “HIV-1 Inhibition by a Peptide,”
Nature
, vol. 365, p. 113 (1993), reported inhibition of HIV-1 with a peptide corresponding to a different portion of the gp41 glycoprotein.
R. Owens et al., “Oligopeptide Inhibitors of HIV-Induced Syncytium Formation,”
AIDS Res. Human Retroviruses
, vol. 6, pp. 1289-1296 (1990) describes the antiviral activity of an analog of the HIV fusion peptide.
While such results are promising, it is typically not possible to extrapolate treatment for one type of virus to other unrelated types: each family of viruses is typically characterized by unique glycoproteins, which may vary within families, or even among variants within a viral “genus.” It is most uncommon to find structural homologues between unrelated or distantly related viral groups, such that an inhibitory compound for one group will also be effective for the other. The variability in envelope structure, type of nucleic acid genome, the arrangement of nucleic acid, and the mechanisms for replicating and packaging the genome are all factors making the treatment of viral disease unpredictable. This variability explains the fact that there are no broad spectrum antiviral agents that might be comparable to broad spectrum antibacterial agents. When considering possible therapeutic regimens, each group of viruses, and even viruses within the same virus family, must be considered separately.
I. A. Wilson, “Structure of the Haemagglutinin Membrane Glycoprotein of Influenza Virus at 3 Å Resolution,”
Nature
, vol. 289, pp. 366-373 (1981) first described the x-ray structure of a viral transmembrane protein, namely that of influenza virus, including the relative positions of the fusion peptide and a helical core structure that organized the glycoprotein complex on the surface of the viral particle.
P. Chambers, “Heptad Repeat Sequences are Located Adjacent to Hydrophobic Regions in Several Types of Virus Fusion Glycoproteins,”
J. Gen. Virology
, vol. 71, pp. 3075-3080 (1990) noted an amphipathic helical motif in the paramyxoviruses, such as measles virus.
E. Delwart et al., “Retroviral Envelope Glycoproteins Contain a ‘Leucine Zipper’-like Repeat,”
AIDS Res. Human Retroviruses
, vol. 6, pp. 703-706 (1990) discussed the structures of several retroviral glycoproteins.
J. Cao, “Changes in the Cytopathic Effects of Human Immunodeficiency Virus Type 1 Associated with a Single Amino Acid Alteration in the Ectodomain of the gp41 Transmembrane Glycoprotein,”
J. Virology
, vol. 68, pp. 4662-4668 (1994), reported that site-directed mutagenesis of one amino acid in the gp41 transmembrane protein of HIV-1 substantially reduced cytopathicity of the virus by reducing fusion activity.
S. Blacklow, “A Trimeric Subdomain of the Simian Immunodeficiency Virus Envelope Glycoprotein,”
Biochemistry
, vol. 34, pp. 14955-14962 (1995) confirmed the trimeric structure of the HIV glycoprotein complex, and the participation of antiparallel amphipathic helices in the formation of those trimers.
D. Lambert, “Peptides from Conserved Regions of Paramyxovirus fusion (F) Proteins are Potent Inhibitors of Viral Fusion,”
Proc. Natl. Acad. Sci. USA
, vol. 93, pp. 2186-2191 (1996) disclosed peptide analogues of putative antiparallel amphipathic helices in paramyxovirus fusion proteins inhibited those viruses.
African Hemorrhagic Fever
African Hemorrhagic Fever (“AHF”) is a viral disease of great concern to the human population. Relatively little is known about the agents that cause AHF. The AHF viruses belong to the Filovirus family, which to date are known to include only Ebola virus and Marburg virus. The Filoviridae family of viruses is characterized by the presence of a single-stranded RNA molecule and RNA transcriptase in the virion.
Human AHF infections have presumably resulted either directly from human contact with the natural reservoir of the agent in the wild, or indirectly from human contact with other primates who have acquired it from the natural reser
Board of Supervisors of Louisiana State University and Agricultu
Parkin Jeffrey S.
Runnels John H.
Scheiner Laurie
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