Agents for the treatment of retroviral infectious diseases
Inventors
Schubert, Ulrich • Setz, Christian • Brysch, Wolfgang • von Wegerer, Jörg
Assignees
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Publication Number
US-10588896-B2
Publication Date
2020-03-17
Expiration Date
Abstract
The invention relates to pyridine-3,5-bis-thiocyanates which are new active substances for the treatment and prevention of retroviral infections and secondary diseases thereof, in particular HIV infections and AIDS, from the group of deubiquitinase inhibitors. Administration of the compounds of the invention increases the immunogenicity of viral proteins and thus the antiviral response.
Core Innovation
The invention relates to pyridine-3,5-bis-thiocyanate DUB-inhibitor agents, including 2,6-diaminopyridine-3,5-bis(thiocyanate), PR-619, and P22077, for treating and preventing retroviral infectious diseases, especially HIV-1 and AIDS. The described agents are positioned as deubiquitinating enzyme inhibitors that target host processes involved in viral life cycle events.
The disclosure describes a host-targeted mode of action by inhibiting deubiquitinating enzymes, with a proposed key role for USP47, to block HIV-1 Gag polyprotein proteolytic processing, including processing of Pr55Gag, and thereby suppress viral replication and spreading. It further states that PR-619 increases immunogenicity of HIV-1 structural proteins by enhancing MHC-I antigen presentation and CD8+ T-cell responses.
Comparative and functional support is described across T cells, macrophages, PBMCs, ex vivo HLAC, and tonsillar tissue, including non-cytotoxic inhibition of HIV-1 replication, dose-dependent MHC-I antigen presentation, and cytotoxicity assessment. The patent also describes supra-additive synergy when PR-619 is combined with proteasome inhibitors bortezomib or PR-957 at very low co-administered doses, and includes treatment and prophylaxis coverage using pharmaceutically acceptable salts, solvates, hydrates, and routes of administration.
Claims Coverage
The provided independent claim covers one main inventive treatment: administering a pharmaceutically effective amount of 2,6-diaminopyridine-3,5-bis(thiocyanate) and pharmaceutically acceptable salts, hydrates, and solvates to an individual with HIV-1 infection. Dependent claims add co-administration with a proteasome inhibitor, with a further narrowing to bortezomib.
Host-targeted HIV-1 treatment with 2,6-diaminopyridine-3,5-bis(thiocyanate)
A method of treating an individual having an HIV-1 infection by administering to such individual a pharmaceutically effective amount of 2,6-diaminopyridine-3,5-bis(thiocyanate) or its pharmaceutically acceptable salts, hydrates, and solvates.
Combination with a proteasome inhibitor for HIV-1 treatment
The method further comprises administering 2,6-diaminopyridine-3,5-bis(thiocyanate) or its pharmaceutically acceptable salts, hydrates, or solvates together with a proteasome inhibitor.
Combination with bortezomib for HIV-1 treatment
The method further comprises administering 2,6-diaminopyridine-3,5-bis(thiocyanate) or its pharmaceutically acceptable salts, hydrates, or solvates together with bortezomib.
Overall, the claim coverage centers on treating HIV-1 infection by administering 2,6-diaminopyridine-3,5-bis(thiocyanate), including pharmaceutically acceptable salts, hydrates, and solvates, optionally as part of combination regimens that include a proteasome inhibitor and, in a narrower refinement, bortezomib.
Stated Advantages
Suppressing viral replication and spreading by blocking HIV-1 Gag polyprotein proteolytic processing.
Avoiding major cytotoxicity at effective doses.
Increasing immunogenicity of HIV-1 structural proteins by enhancing MHC-I antigen presentation and CD8+ T-cell responses.
Providing supra-additive synergistic effect when PR-619 is combined with proteasome inhibitors bortezomib or PR-957 at low subthreshold concentrations.
Nearly complete inhibition of HIV-1 replication at non-cytotoxic concentrations for PR-619 and P22077.
Inhibition specificity linked to USP47 as the common actionable DUB target.
Minimal toxicity at antiviral concentrations for PR-619 and bortezomib, and combination does not cause added cytotoxicity.
Combined treatment does not bias host cell vitality in ex vivo tonsillar tissue.
Documented Applications
Treating an individual having an HIV-1 infection using 2,6-diaminopyridine-3,5-bis(thiocyanate) or its pharmaceutically acceptable salts, hydrates, and solvates.
Treating HIV-1 infection with 2,6-diaminopyridine-3,5-bis(thiocyanate) in combination with a proteasome inhibitor.
Treating HIV-1 infection with 2,6-diaminopyridine-3,5-bis(thiocyanate) in combination with bortezomib.
Treating and preventing retroviral infections, especially HIV-1/AIDS, and associated sequelae.
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