Nucleotide triphosphatase/helicase of hepatitis C virus as a target for antiviral therapy

Abstract

The RNA nucleoside triphosphatase (NTPase)/helicases represent a large family of proteins that are detected in almost all biological systems where RNA plays a central role. The enzymes are capable of enzymatically unwinding duplex RNA structures by disrupting the hydrogen bonds that keep the two strands together. The strand separating activity is associated with hydrolysis of nucleoside triphosphate (NTP). Because of this, potential specific inhibitors of NTPase/helicases could act by one or more of the following mechanisms: (i) inhibition of NTPase activity by interference with NTP binding, (ii) inhibition of NTPase activity by an allosteric mechanism and (iii) inhibition of the coupling of NTP hydrolysis at the unwinding reaction. There are also other inhibitory mechanisms conceivable, which may involve a modulation of the interaction of the enzyme with its RNA substrate, for example, (iv) the competitive inhibition of RNA binding and (v) the inhibition of the unwinding by sterical blockade of the translocation of the NTPase/helicase along the polynucleotide chain. NTPase/helicase has also been identified in the viral genome of hepatitis C virus (HCV) which is a member of the Flaviviridae family. It is conceivable that the inhibition of the unwinding activity of the enzyme leads to the inhibition of virus replication and this may represent a novel antiviral strategy. This review updates the current spectrum of inhibitors targeting different mechanisms by which the NTPase and/or helicase activities of the HCV NTPase/helicase are inhibited. Consequently, some of the compounds might be important as antiviral agents against HCV.