Drug Development

BioDrugs

, Volume 17, Issue 3, pp 169-177

Stealth Nucleosides

Mode of Action and Potential Use in the Treatment of Viral Diseases

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Abstract

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.