Antiviral JAK inhibitors useful in treating or preventing retroviral and other viral infections
Inventors
Gavegnano, Christina • Schinazi, Raymond F.
Assignees
US Department of Veterans Affairs
Publication Number
US-10821111-B2
Publication Date
2020-11-03
Expiration Date
2032-11-30
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Abstract
Compounds, compositions, and methods of treatment and prevention of HIV infection are disclosed. The compounds are pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrimidine JAK inhibitors. Combinations of these JAK inhibitors and additional antiretroviral compounds, such as NRTI, NNRTI, integrase inhibitors, entry inhibitors, protease inhibitors, and the like, are also disclosed. In one embodiment, the combinations include a combination of adenine, cytosine, thymidine, and guanine nucleoside antiviral agents, optionally in further combination with at least one additional antiviral agent that works via a different mechanism than a nucleoside analog. This combination has the potential to eliminate the presence of HIV in an infected patient.
Core Innovation
The invention provides compounds, compositions, and methods of treatment and prevention of HIV infection, specifically involving pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrimidine JAK inhibitors. The invention includes combinations of these JAK inhibitors with additional antiretroviral compounds, including nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), integrase inhibitors, entry inhibitors, protease inhibitors, among others.
The problem addressed by the invention arises from the limitations of current HIV treatments. Although synthetic nucleosides and combination therapies like HAART have reduced HIV mortality and progression, none eliminates HIV completely due to latent reservoirs and emergence of multidrug resistance. Existing drugs are often toxic and require complex regimens, reducing patient compliance and effectiveness. There remains an unmet need for therapies that minimize virological failure, reduce resistance development, and potentially cure HIV/AIDS by eradicating virus from all reservoirs.
The invention provides methods and compositions that include JAK inhibitors which function through mechanisms distinct from conventional antiretroviral therapies. The combination of these JAK inhibitors with nucleoside antiviral agents covering all four bases (adenine, cytosine, thymidine, guanine) and other antiviral agents having different mechanisms reduces the ability of HIV to develop resistance. Administration early in infection stages may allow elimination of HIV. JAK inhibitors also have the potential to augment treatment efficacy, minimize required doses, and reduce toxicity through synergistic or alternation therapy with other antiviral agents. Moreover, they may inhibit activation and reactivation of latent virus reservoirs.
Claims Coverage
The claims include multiple inventive features focusing on methods for treating or eradicating HIV infection using compounds defined by chemical Formula B and their combinations with other antiviral agents and therapies.
Use of compounds of Formula B to treat HIV infection
A method for treating an HIV infection by administering an effective antiviral amount of a compound of Formula B to a patient in need thereof.
Combination therapy with multiple antiviral agents
Co-administration of the compound of Formula B with (a) at least one each of adenine, cytosine, thymidine, and guanine nucleoside antiviral agents or (b) at least one additional antiviral agent selected from NNRTI, protease inhibitors, fusion inhibitors, entry inhibitors, attachment inhibitors, and integrase inhibitors.
Use of a macrophage depleting agent in combination with JAK inhibitors and HAART
A method involving reducing viral loads with HAART and a JAK inhibitor, systemically depleting macrophages with a macrophage depleting agent (e.g., Boniva or Fosamax) while maintaining HAART and JAK inhibitor therapy, then withdrawing the macrophage depleting agent, followed by withdrawal of HAART and/or JAK inhibitor therapy while optionally monitoring viral rebound.
Use of reactivation agents in combination with JAK inhibitors and HAART
A method of treating or eradicating HIV by reducing viral loads using HAART and a JAK inhibitor, administering a reactivation agent (e.g., panobinostat) while maintaining HAART and/or JAK inhibitor therapy, then withdrawing the reactivation agent upon increased viral loads and continuing treatment with HAART and the JAK inhibitor, followed by withdrawal of HAART and/or JAK inhibitor therapy while optionally monitoring viral rebound.
Combination with anti-HIV vaccines and immunomodulatory agents
Treating or eradicating HIV by administering a JAK inhibitor and an anti-HIV vaccine and/or an immunostimulatory or immunomodulatory agent before, during, or after administration of the JAK inhibitor, optionally combined with HAART that includes multiple antiviral agents.
The independent claims cover the use of compounds of Formula B to treat HIV infection, both alone and in combination with various antiviral agents, macrophage depleting agents, reactivation agents, vaccines, and immunomodulatory agents. The claims detail methods involving combination or alternation therapies to improve antiviral efficacy and address latent virus reservoirs.
Stated Advantages
JAK inhibitors provide potent antiviral activity against HIV-1 and HIV-2 with wide therapeutic windows and low toxicity.
Combination therapy with JAK inhibitors and multiple nucleoside antiviral agents minimizes viral resistance development.
JAK inhibitors function via mechanisms distinct from conventional NRTI, NNRTI, protease, and integrase inhibitors, reducing likelihood of resistance.
Synergistic action of JAK inhibitors with other antiviral agents allows reduced effective dosages, thereby reducing toxicity.
JAK inhibitors inhibit reactivation of latent HIV reservoirs, aiding in potential eradication of virus.
Certain JAK inhibitors inhibit CYP3A4, thereby increasing plasma levels of co-administered antiviral drugs, potentially enhancing efficacy.
Combination therapies including macrophage depletion, reactivation agents, vaccines, and JAK inhibitors offer strategies towards curing HIV infection.
Documented Applications
Treatment and prevention of HIV infection, including HIV-1 and HIV-2.
Use against drug resistant HIV strains including M184V/I, multidrug resistant viruses, K65R mutation, and thymidine analog mutations (TAM).
Combination therapy approaches incorporating JAK inhibitors with all four nucleoside analog bases (adenine, cytosine, thymidine, guanine), NNRTIs, protease inhibitors, fusion inhibitors, entry inhibitors, attachment inhibitors, and integrase inhibitors.
Prevention and treatment of related conditions such as AIDS-related complex, persistent generalized lymphadenopathy, AIDS-related neurological conditions, Kaposi's sarcoma, thrombocytopenia purpurea, and opportunistic infections.
Prophylactic use in individuals positive for anti-HIV antibodies or antigen, or exposed to HIV.
Treatment or prevention of other viral infections including Flaviviridae infections such as HCV, Dengue virus, Japanese encephalitis virus group, Yellow Fever virus, Pestivirus genus, and Alphaviruses such as Chikungunya virus.
Combination therapies including macrophage depleting agents (e.g., clodronate-loaded liposomes, gadolinium chloride, Boniva, Fosamax), histone deacetylase inhibitors, interleukin 7, vaccines or immunostimulatory/immunomodulatory agents.
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