Combination chemotherapy for influenza

Abstract

The emergence of pandemic H1N1 influenza viruses in April 2009 and the continuous evolution of highly pathogenic H5N1 influenza viruses underscore the urgency of novel approaches to chemotherapy for human influenza infection. Anti-influenza drugs are currently limited to the neuraminidase inhibitors (oseltamivir and zanamivir) and to M2 ion channel blockers (amantadine and rimantadine), although resistance to the latter class develops rapidly. Potential targets for the development of new anti-influenza agents include the viral polymerase (and endonuclease), the hemagglutinin, and the non-structural protein NS1. The limitations of monotherapy and the emergence of drug-resistant variants make combination chemotherapy the logical therapeutic option. Here we review the experimental data on combination chemotherapy with currently available agents and the development of new agents and therapy targets.

Keywords: amantadine; antivirals; combination therapy; influenza virus; neuraminidase inhibitors; oseltamivir; ribavirin.

Figure 1.

Benefits of combination therapy for influenza. Combination therapy could target different viral proteins (A) that have different mechanisms of antiviral action (for example, NA inhibitor and M2 ion channel blocker), or (B) target virus and host factors that affect virus replication and host defense mechanisms (for example, NA inhibitor and immunomodulator). This diagram represents only double drug combinations, but a multidrug approach could consist of three or more drugs in combination. Abbreviations: HA- hemagglutinin; NA - neuraminidase; M2 - matrix protein.

Figure 2.

Schematic representation of influenza virus replication cycle and sites of action of antiviral agents. Note. Influenza A virus contains eight RNA segments of negative polarity coding for at least 11 viral proteins. The surface proteins of influenza A virus consist of two glycoproteins, hemagglutinin (HA) and neuraminidase (NA), and the M2 protein. The HA protein attaches the virus to sialic acid–containing receptors on the cell surface and initiates infection. A fusion protein inhibitor (DAS-181) targets the influenza virus receptor in the host respiratory tract and inhibits virus attachment. Cyanovirin-N (CVN) binds to high-mannose oligosaccharides on HA and inhibits the entry of virus into cells. For most influenza A viruses, the M2 ion channel blockers (amantadine and rimantadine) impede viral replication at an early stage of infection after penetration of the cell but prior to uncoating. M2 blockers inhibit the decrease in pH within the virion and thus block the release of viral RNA into the cytoplasm and prevent transportation of the viral genome to the nucleus. Inhibition of the viral polymerase, an essential component of viral RNA replication in the nucleus, can be blocked by the polymerase inhibitors ribavirin and T-705. Small interfering RNAs (siRNAs) that target different viral genes can inhibit viral replication. Several mechanisms of action have been proposed for the anti-influenza virus activity of ribavirin. One is the inhibition of the cellular enzyme inosine monophosphate dehydrogenase, resulting in a decrease in the intracellular guanosine 5’-triphosphate (GTP) that is required for nucleic acid synthesis. Ribavirin triphosphate also inhibits the function of virus-coded RNA polymerases which are necessary to initiate and elongate viral mRNAs. Late in infection, NA cleaves sialic acid–containing receptors and facilitates the release of budding virions. NA inhibitors (zanamivir, oseltamivir, peramivir, and LANI) block NA activity, preventing the release of virions from the cell.