In order to understand where a next breakthrough in HIV/AIDS treatment might be expected, it is necessary to understand the complexity of this viral pathogen and consequently the inherent limitations of the therapeutics that are currently available or could be developed to challenge this disease.
- Rather than mitigating apoptosis in active CD4+ T cells such as provoked by Protease Inhibitors, our Translation Inhibitor class of DDX3 helicase inhibiting compounds does not have such a mitigating mechanism and will even most likely promote cellular apoptosis.
Unlike Protease Inhibitors, which actually allow newly formed virions to exit the cell, albeit with dysfunctional viral proteins, Translation Inhibitors effectively block the production of new virions by the inhibition of the DDX3 helicase enzyme, a vital co-factor of the host cell’s protein apparatus, hijacked by the virus, during its translation from proviral host cell DNA. This way, viral components remain trapped within the cell because the synthesis of the essential polyproteins is disrupted. As such, the tentative formation of new viral particles from proviral DNA inevitably leads to the accumulation of unspliced mRNA in the nucleus and spliced mRNA and polyprotein material in the cellular cytoplasm. A part of the protein material will likely be re-metabolised, but the accumulation of cellular waste is generally known to be a pro-apoptotic mechanism. Repeated failed attempts to produce new virions will inevitably accumulate ever more viral waste within the host cell and ultimately promote apoptosis.
Improved resistance profile
- Another quality of Translation Inhibitor ART treatment that is of inestimable value is its potential to prevent the rapid resistance development commonly associated with antiretroviral treatments. Resistance development in traditional ART medication is promoted by alterations of the viral protein apparatus induced by genetic survival of flawed Transcriptase, Integrase and Protease Inhibition attempts. Since viral Translation Inhibition does not involve any viral proteins, but rather a RNA Helicase enzyme proprietary to the host cell’s protein apparatus, the virus finds itself incapable of modifying the DDX3 host cell protein that is indispensable for the translation of the proviral DNA into new functional viral particles. As part of its preclinical development our DDX3 Helicase inhibitor class of compounds was tested against several viral strains that were resistant towards each class of the known ART medications and proved to be effective at sub-micro-molar concentrations against all ART resistant strains.
Combination Treatment Strategy
- It should be clear that Translation Inhibitor antiretroviral agents have a lot going for them in being applied as a standalone ART treatment, however their greatest contribution to the battle against HIV might very well be as a combination medication in a strategic approach aiming towards a total eradication of the virus in the human body. We already know that traditional HAART treatment is perfectly capable of reducing the viral load in the vascular system to minimal levels. As such, a “pre-cleaning” by HAART, followed by Translation Inhibiting therapy, in combination with a wake-up agent for dormant reservoir cells, could very well prove to be the road to take towards total HIV eradication. The war against HIV is not won yet and it will require joint efforts from many sides, but our novel Translation Inhibitor class of ART compounds offer a true perspective of a better future for millions of HIV/AIDS patients worldwide.
HIV antiviral activity of Translation Inhibitors
- Antiviral efficacy is usually measured by means of Single-step Growth Curve assays and typically studies a single viral replication cycle in which a monolayer of tissue culture cells is contemporarily infected with a high multiplicity of infection (MOI) (on average 10 viruses per cell), in order to guarantee contemporary infection of all cells in the monolayer. This standard method was also used in the efficacy assays discussed above. Considering however that the DDX3 Helicase inhibiting antiviral mechanism of our technology does neither interfere with viral entrance, nor with any of the viral enzymatic factors. In theory, this method doesn’t do right to our compounds. As such, we used a different method and measured the antiviral efficacy after the second replication cycle, by which the result of our cellular co-factor inhibiting mechanism of action should be noticeable.
The results of these assays are very positive. These so-called (sub) micro-molar results are fully in line with the equally impressive enzymatic inhibitory activity of our hit compounds. Considering the also excellent cytotoxicity values, we are already pursuing our HIV antiviral candidates into further in-vivo testing and preclinical development.