Antiviral Therapies: toxicity and drug resistance

Therapies based on nucleotide analogs bear two caveats.

• One is their potential toxicity for the patient.Most of our selected nucleotide analogs are devoid of cytotoxicity.
  As far as genotoxicity is concerned, our nucleotide analogs have been selected for their ability to be substrates for viral polymerases, but not for cellular polymerases, including Pol gamma (mitochondrial). Hence toxicities may be of no or only minor concern, as has been shown by toxicogenomics in human hepatic cell cultures exposed to several of the selected active nucleotide analogs (see HT tToxicogenomics section of Vigilent Technologies).
• The second problem is drug resistance, which is the rule with present-day antiviral medications.
  For instance, when treating HIV1 or HCV infected patients with nucleotide analogs devoid of OH linked to C3’, elongation of the nascent chain aborts. The virus is then forced to explore its genetic repertoire and find mutations that can resist and overcome the abortion, thereby developing drug resistance.
  To the contrary, our nucleotide analogs do not block elongation of the nascent chain, allowing the viral polymerase is able to proceed and incorporate the next nucleotide without any selectivity pressure. This does however not warrant elongation of an additional nucleotide. Indeed, in RNA double helices, ribose pucker is usually C3’ endo. If a C3’ endo nucleotide is paired to a C2’ endo analog, the double helix will display a strong bend. Consequently, if a nucleotide analog attached to the nascent chain is C2’ endo, chances are that, for the next nucleotide, the triphosphate group at C5’ is displaced from the active site of the polymerase, due to the induced bend. Processivity would then be abolished one or two nucleotides passed the incorporation of the C2’ endo nucleotide analog.

Our therapies deal primarily with therapies against HIV1 and other retroviruses or pararetroviruses (HBV), but target also many RNA virus quasi-species. The patents also claim provision for appending triphosphate C5’ of the nucleotide analogs and their formulations as prodrugs.

For a decade now, several publications have described antiviral activities of nucleotide analogs sharing precisely the basic concept of our patents, mainly those active against HCV and Ebola. They provide proof that this concept is valid and can be successfully applied to viral quasi-species.