Viral and cellular RNA helicases as antiviral targets

Key Points

• To date, although many viral infections can be successfully prevented via vaccination, we lack effective knowledge of vaccines for numerous important human pathogens, including hepatitis C virus (HCV) and human immunodeficiency virus (HIV). Accordingly, antiviral drugs will be needed to treat many viral diseases. Virally encoded enzymes and cellular enzymes adapted for use by viruses for replication might represent useful targets for antiviral drugs.

• Drugs that target either a viral or cellular polypeptide hold different implications. Inhibitors of unique viral functions have a lower risk of toxicity, whereas inhibitors of cellular enzymes that are used by viruses have a narrower window for efficacy without creating toxicity.

• All viruses seem to require a helicase function for replication. HCV encodes a viral RNA helicase, and recent findings have shown that HIV-1 adapts a cellular RNA helicase for its viral lifecycle. These observations raise the possibility of small-molecule helicase inhibitors as a general mode of antiviral therapy.

• Helicases fall into three super-families (SF1, SF2 and SF3) with conserved motifs. The conserved motifs are associated with conserved helicase function. However, outside of the conserved motifs the primary sequences and tertiary structures between helicases are differ greatly. In this regard, differences in primary sequence and tertiary structure between the helicase of a viral pathogen and that of cellular helicases can be exploited to confer specificity to an antiviral inhibitor.

• The conformation of an active helicase can be broadly divided into an 'open' and a 'closed' complex. Strategies for identifying small-molecule helicase inhibitors include: inhibiting NTPase activity by direct competition with NTP binding; competitively inhibit nucleic-acid binding; inhibiting NTP hydrolysis or NDP release by blocking the movement of domain 2; inhibiting the process that couples NTP hydrolysis to translocation and unwinding of nucleic acid; inhibiting unwinding by sterically blocking helicase translocation; and inhibiting unwinding. Other potential inhibitory mechanisms include those that change the physical conformation of the helicase, or those that disrupt helicase turnover, or those that inhibit helicase interaction with other crucial proteins.

• Preclinical proof of concept for helicase inhibitors as antiviral agents has been obtained for HSV. This breakthrough finding provides the best evidence to date that it is possible to develop selective, potent inhibitors of a viral helicase as antiviral agents. Searches are ongoing for antihelicase molecules that have activity against HCV or HIV-1.

Abstract

Although there has been considerable progress in the development of antiviral agents in recent years, there is still a pressing need for new drugs both to improve on the properties of existing agents and to combat the problem of viral resistance. Helicases, both viral and human, have recently emerged as novel targets for the treatment of viral infections. Here, we discuss the role of these enzymes, factors affecting their potential as drug targets and progress in the development of agents that inhibit their activity using the hepatitis C virus-encoded helicase NS3 and the cellular helicase DDX3 adopted for use by HIV-1 as examples.