Riboviruses and retroviruses have been shown to spontaneously mutate at an extraordinarily high rate. While this genetic diversity allows viral subpopulations to escape conventional
antivirals, it also has a cost. Indeed, this high mutation rate results in the synthesis of many defective virions. Stealth
nucleosides are
nucleoside analogues that are designed to increase the already high spontaneous mutation rate of viruses to the point where the virus cannot further replicate, a process known as "lethal mutagenesis". Rather than causing chain termination and attempting to immediately halt viral replication, as with conventional
nucleoside reverse transcriptase inhibitors (NRTI), stealth
nucleosides are incorporated into the viral genome during replication and, by mispairing, cause mutations to the viral genome. These mutations affect all
viral proteins and cumulatively, over a number of replication cycles, are lethal to the virus. There are two distinct stealth
nucleoside platforms:
DNA stealth
nucleosides and
RNA stealth
nucleosides.
DNA stealth
nucleosides are currently being screened for activity against HIV and may have activity against hepatitis B virus and smallpox virus, with the clinical lead
DNA stealth
nucleoside demonstrating activity in the low nanomolar range. In addition,
DNA stealth
nucleosides have been shown to be able to effectively treat NRTI-resistant HIV strains in vitro, which is not surprising given that the two principal modes of resistance (low affinity of
reverse transcriptase for a modified
sugar or pyrophosphorolysis) should not be applicable to
DNA stealth
nucleosides.
RNA stealth
nucleosides are being developed for the treatment of ribovirus
infections, and particularly hepatitis C virus
infection.
RNA stealth
nucleosides are selected for their broad spectrum of
antiviral activity, and current lead
RNA stealth
nucleosides have potency in the same range as
ribavirin.