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Antiviral inhibition of capsid proteins

Antiviral inhibition of capsid proteins description/claims

This application claims priority to U.S. provisional application No. 60/374,557 filed Apr. 22, 2002, U.S. provisional application No. 60/375,852 filed Apr. 25, 2002 and U.S. provisional application No. 60/404,043 filed Aug. 16, 2002.

The U.S. Government has a paid-up license in this invention and the right in limited circumstances to require the patent owner to license others on reasonable terms as provided for by the terms of grant no. A130917 awarded by the National Institutes of Health.

The invention relates to treatment of Acquired Immunodeficiency Syndrome (AIDS). In particular, the invention relates to treatment of AIDS by inhibition of the Human immunodeficiency virus type 1 (HIV-1) capsid protein.

Viruses are noncellular infective agents that are capable of reproducing only in an appropriate host cell. Viruses are typically smaller than bacteria, and can infect animal, plant, or bacterial cells. Many viruses are important agents of disease. The infective particle (virion) consists of a core of nucleic acid surrounded by a proteinaceous capsid and, in some cases, an outer envelope.

Retroviruses are enveloped single-stranded RNA viruses infecting animals. The family consists of three groups: the spumaviruses such as the human foamy virus; the lentiviruses, such as the human immunodeficiency virus types 1 and 2, as well as visna virus of sheep; and the oncoviruses.

The retrovirus particle is composed of two identical RNA molecules. Each genome is a positive sense, single-stranded RNA molecule, which is capped at the 5′ end and polyadenylated at the 3′ tail. The prototype C-type oncoviral RNA genome contains three open reading frames call gag, pol and env, bounded by regions that contain signals essential for expression of the viral genes. The gag region encodes the structural proteins of the viral capsid. The pol region encodes a viral proteinase as well as the proteins for genome processing, including reverse transcriptase, ribonuclease H and endonuclease enzymatic activities. The env region specifies the glycoproteins of the viral envelope. In addition to these three open reading frames, the more complex genomes of the lentiviruses and the spumaviruses carry additional open reading frames which encode regulatory proteins involved in the control of genome expression.

There are substantial homologies between the capsid proteins of both viruses and retroviruses. One of skill in the art can easily identify these homologies by searching any of the standard biotechnology search engines.

AIDS is a retroviral disease characterized by profound immunosuppression that leads to opportunistic infections, secondary neoplasms and neurologic manifestations. The magnitude of this modern plague is truly staggering. In the United States, AIDS is the leading cause of death in men between 25 and 44 years of age, and it is the third leading cause of death of women in this age group. Although initially recognized and reported in the United States, it has now been reported from more than 193 countries around the world. The pool of HIV-infected persons in Africa and Asia is large and rapidly expanding. Transmission of HIV occurs under conditions that facilitate exchange of blood or body fluids containing the virus or virus-infected cells. Hence, the three major routes of transmission are sexual contact, parenteral inoculation, and passage of the virus from infected mothers to their newborns. Because of the almost uniformly fatal outcome of AIDS, finding effective treatments for the disease remains a serious medical problem.

There is little doubt that AIDS is caused by HIV, a nontransforming human retrovirus belonging to the lentivirus family. O'Brien, et al., HIV causes AIDS: Koch's postulates fulfilled, Curr Opin Immunol 8:613 (1996). Two genetically different but related forms of HIV, called HIV-1 and HIV-2, have been isolated from patients with AIDS. HIV-1 is the most common type associated with AIDS in the United States, Europe, and Central Africa, whereas HIV-2 causes similar disease principally in West Africa.

Similar to most retroviruses, the HIV-1 virion is spherical and contains an electron-dense, cone shaped core surrounded by a lipid envelope derived from the host cell membrane. The virus core contains (1) the major capsid protein p24 (CA), (2) nucleocapsid protein p7/p9, (3) two copies of genomic RNA, and (4) the three viral enzymes (protease (PR), reverse transcriptase (RT), and integrase). The viral core is surrounded by a matrix protein called p17, which lies underneath the virion envelope. Studding the viral envelope are two viral glycoproteins, gp 120 and gp 41, which are critical for HIV infection of cells.

As with other retroviruses, the HIV proviral genome contains the gag, pol, and env genes, which code for various viral proteins. The products of the gag and pol genes are translated initially into large precursor proteins that must be cleaved by the viral protease to yield the mature proteins.

The CA is initially synthesized as a domain within a 55 kDa Gag precursor polyprotein. Approximately 4,000 copies of Gag assemble at the plasma membrane and bud to form an immature virus particle. Subsequent to budding, the CA is liberated by proteolytic cleavage of Gag, which triggers a conformational change that promotes assembly of the capsid particle. Gitti, et al., Structure of the amino-terminal core domain of the HIV-1 capsid protein, Science, 273: 231-35 (1996); von Schwedler, et al., Proteolytic refolding of the HIV-1 capsid protein amino-terminus facilitates viral core assembly, EMBO J., 17: 1555-68 (1998); Gross, et al., N-terminal extension of human immunodeficiency virus capsid protein converts the in vitro assembly phenotype from tubular to spherical particles, J. Virol., 72: 4798-4810 (1998). Two copies of the viral genome and enzymes essential for infectivity become encapsidated in the central, cone shaped capsid of the mature virion.

Several recent studies have shown that proper capsid assembly is critical for viral infectivity. Mutations in CA that inhibit assembly are lethal and mutations that alter capsid stability severely attenuate replication making the CA an attractive potential antiviral target. Tang, et al., Human immunodeficiency virus type 1 N-terminal capsid mutants that exhibit aberrant core morphology are blocked in initiation of reverse transcription in infected cells, J. Virol. 75: 9357-66 (2001); Reicin, et al., The role of Gag in human immunodeficiency virus type 1 virion morphogenesis and early steps of the viral life cycle, J. Virol., 70: 8645-52 (1996); and Forshey, et al., Formation of a human immunodeficiency virus type 1 core of optimal stability is crucial for viral replication, J. Virol. 76: 5667-5677 (2002).

Although antiviral agents have been developed that bind to the capsid protein of picornaviruses and suppress infectivity by inhibiting disassembly of the capsid shell, Smith, et al., The site of attachment in human rhinovirus 14 for antiviral agents that inhibit uncoating, Science, 233: 1286-93 (1986), inhibitors of HIV capsid assembly or disassembly have not yet been identified. Currently available drugs for the treatment of HIV infection target the RT and PR enzymes, two of fifteen proteins encoded by the viral genome. These drugs are marginally effective when administered independently due to the rapid emergence of resistant strains that are selected under conditions of incomplete viral suppression. Richman, D. D., HIV chemotherapy, Nature 410: 995-1001 (2001). Although sustained reductions in viral load can be achieved when inhibitors are used in appropriate combinations (highly affective anti-retroviral therapy, HAART), Richman, D. D., HIV chemotherapy, Nature 410: 995-1001 (2001); Pillay, et al, Incidence and impact of resistance against approved antiretroviral drugs, Rev Med Virol, 10: 231-53 (2000), inadequate suppression due to poor compliance, resistance, and interactions with other drugs or diet is a significant problem that limits the effectiveness of HAART therapy for many patients and can lead to the spread of drug-resistant strains. Mansky, et al, Combination of drugs an drug-resistant reverse transcriptase results in a multiplicative increase of human immunodeficiency virus type 1 mutant frequencies, J. Virol., 76: 9253-59 (2002); Coffin, J., HIV population dynamic in vivo: implications for genetic variation, pathogenesis, and therapy, Science, 267: 483-89 (1995); Kuritzkes, D. R., Clinical significance of drug resistance in HIV-1 infection, AIDS, 10: S27-33 (1996).

In spite of the availability of HAART therapy, the mortality and morbidities associated with AIDS remain significant and unresolved by current therapies. New therapeutic compounds and methods are needed that could reduce or ameliorate the adverse events and improve the clinical outcome of AIDS, including, for example, reducing mortality and improving the quality of life of those suffering from the disease.

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