Antiviral Therapies: the Iolas Strategy

It is known since ancient times that a reward strategy to get rid of an aggressive enemy is to turn his own weapons against him (1).
In the present case, to get control over viral quasi-species, it would be enough to get hold of their fidelities and processivities, so as to move a given quasi-species virus away from its consensus sequence. Vigilent's patents build precisely on this concept.

Killing RNA viruses like HCV, HIV etc., is spontaneously opposed by the viral high mutation, and low processivity, rates, key factors allowing the virus quasi-species to overcome any antiviral challenge. To the contrary, if control over its mutation and processivity rates is lost by the virus and taken over by medications, the virus can be forced to commit suicide.
To this end, two "suicidal" menu options are offered to the virus:

  • Either upon marginally increasing its mutation rate, the virus loses infectivity and clears the host’s body due to lack of progeny (a strategy later dubbed as "viral error catastrophe");
  • Or, to the contrary, upon reducing its mutation rate, the virus becomes stabilized into one or a few stable strains (reinforced fidelity), allowing conventional viral clearance by the immune system and/or conventional antiviral drugs. This latter option is of interest, since it would immunize the patient against these strains.

Vigilent proposes patented RNA virus therapies based on nucleotide analogs (1) that are substrates of RNA-dependent viral polymerases, (2) bearing an OH group on the C3’ carbon of its ribose sugar moiety, and (3) enabling the nucleic acid polymerization to proceed.

Unlike "passive"(2) nuclotide analogs traditionally used to force polymerization termination in antiviral therapies, these nucleotide analogs are "active" in the polymerization process. Our laboratory has a treasury of hundreds of powerful active viral "suicide" drug candidates in its pipeline, which can be split into two categories: those enabling mutations, and those modifying processivities of the viral polymerases. We also have a number of active nucleotide analogs able to stabilize viral quasi-species strains.

The general strategy described in our patents is generic and can be applied to the treatment of diseases due to viral quasi-species, in particular RNA virus quasi-species, whether direct RNA viruses with positive polarity (Coronaviridae, Flaviviridae) or negative polarity (Filoviridae, Togaviridae, Bunyaviridae, Arenavirus, Paramyxoviridae, Orthomyxoviridae).

About one human in 5 (some 1.5 billion world-wide) is affected by diseases involving these viral species. For a decade now, several publications have described antiviral activities of active nucleotide analogs sharing precisely those basic concepts, in particular those active against HCV and Ebola.

(1) Iolas is a Greek mythological character who assisted Hercules in his fight against the Hydra of Lerne, famous for its ability to regenerate and spit fire. As Hercules cut a head of the Hydra, two more heads spitting fire emerged. Iolas understood that the only way out would be to expose the hydra to its own strategy: fire. He burned the throat of the monster just after beheading, and Hercules triumphed.
(2) "Passive" nucleotide analogs end polymerization due to the lack of OH at C3’. Passive nucleotide analogs are used to prevent viral replication. On the contrary, "active" nucleotid analogs do not end polymerization : they are used to silently induce arbitrary modifications in the resulting genome.