Inhibitors of Retroviral Replication

Abstract

Methods for preventing or treating retroviral infection, such as human immunodeficiency virus, in vivo utilize transcriptional inhibitory compounds. These include cortistatin A and analogs of the cortistatin family.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001]The present application claims the priority of U.S. provisional patent application No. 61 / 431,198 filed Jan. 10, 2011 and entitled “CORTISTATIN A IS AN INHIBITOR OF HIV REPLICATION”, which is incorporated herein by reference in its entirety.FIELD OF THE INVENTION [0002]Embodiments of the invention comprise methods for preventing or treating retroviral infection, such as human immunodeficiency virus (HIV), human T-cell leukemia virus (HTLV). Further embodiments comprise compounds which modulate Tat-TAR interactions, the functions or activities of Trans-Activator of Transcription (Tat) or Transactivation Responsive elements (TAR), molecules associated with Trans-Activator of Transcription (Tat) or Transactivation Responsive element (TAR).BACKGROUND [0003]Although treatment with antiretroviral drugs (ARVs) has extended the quality and expectancy of life for people infected with human immunodeficiency virus (HIV), they have been unsuccessful...

AI Technical Summary

Benefits of technology

This patent is about pharmaceutical compositions that contain drugs that can prevent or treat viral infections, specifically HIV and HTLV. The drugs target a protein called Tat, which is involved in the process of retroviral transcription. The invention uses cortistatins and analogs to inhibit the function of Tat and prevent the infection from spreading. The technical effect of this invention is to provide a novel therapeutic approach for treating viral infections, particularly HIV and HTLV.

Problems solved by technology

Although treatment with antiretroviral drugs (ARVs) has extended the quality and expectancy of life for people infected with human immunodeficiency virus (HIV), they have been unsuccessful in curing HIV infection.

Highly active antiretroviral therapy (HAART) is based on triple or quadruple combinations of ARVs, however while reducing HIV to very low levels, this treatment fails to eliminate the infection completely (Clavel F.

Because Tat is crucial for virus replication, it is the target for the development of, several active compounds; however these showed low efficacy and none has yet been reported to have completed clinical trials.

Highly active antiretroviral therapy (HAART) is based on triple or quadruple combinations of NRTIs, NNRTIs and PIs and while reducing HIV to very low levels, fails to eliminate the infection completely and ultimately leads to the emergence of drug-resistant mutant strains.

The modified Pol II clears the promoter and starts transcription of TAR, but Pol II stalls right after initiation and is inefficiently converted into the processive form.

Other molecules such as trans-dominant Tat mutants, TAR RNA analogs, antisense oligonucleotides, ribozymes, and polypeptides have all been used to inhibit the interaction between Tat and TAR or Tat and other cellular co-activators; but none of them is currently used in therapeutics partly because some of these strategies may not easily be delivered for an efficient therapy, emphasizing the need for small molecule compounds.

No natural compounds have ever been previously shown to inhibit HIV replication in human test subjects.

Although treatment with antiretroviral drugs (ARVs) has extended the quality and expectancy of life for people infected with HIV, it has been unsuccessful in curing HIV infection.

Highly active antiretroviral therapy (HAART) is based on triple or quadruple combinations of ARVs, however while reducing HIV to very low levels, this treatment fails to eliminate the infection completely.

A desirable Tat inhibitor should block Tat-mediated activation of the viral promoter without affecting its basal transcription, which would result in cellular toxicity, given the shared transcription factors of the HIV promoter and cellular genes.

Furthermore dCA, but not other ARVs, reduced viral RNA levels in the lymphocytic cell line CEM SS chronically infected with pNL43 (FIG. 1H), demonstrating that the effect of dCA is not only cell-type independent but also that they extend to the reduction of viral expression from cells already infected, a result that none of the currently used ARVs is able to achieve.

First, lymphocytes isolated from infected patients show abnormal nucleolar structure, and second, nucleolar localization of TAR impairs virus replication.

It was observed that even in the absence of drug, elongation from the HIV-1 viral promoter is not very efficient.

Overall, these provide evidence that dCA promotes rapid and permanent silencing of the HIV promoter, which may drastically limit the emergence of dCA-resistant viruses.

PIs show low efficacy in this short 48 h assay as they act only upon spreading from the initial infection.

Given that dCA blocks a post-integration event, this result is unsurpassing and it compares favorably with late acting compounds such as PIs.

Moreover, inhibition of CDK11 activity would be expected to be toxic, as CDK11 knockdown severely impairs cellular viability, and at the nanomolar concentrations of CA at which it was reported to interact with CDK11.

Low levels of viral production persist in HIV-infected subjects taking HAART and are a major obstacle for complete eradication of the infection. dCA treatment was extremely successful at reducing viral production by a drastic 99.7% from primary CD4+ T cells isolated from aviremic patients who had been under HAART treatment for a long period of time.

There is no evidence that neurons are infected with the virus; however, neuronal damage and dropout occur, indicating that neuronal cell death must be the result of indirect mechanisms, such as neurotoxins released by HIV-infected and uninfected cells.

It is unclear whether the majority of the detected tat is released by infected cells within the CNS or is specifically transported across the blood-brain barrier (BBB) from the sera, but either way tat is taken up by CNS cells with toxic consequences often resulting in apoptosis, particularly in neurons.

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