Drugs in development for influenza

Abstract

The emergence and global spread of the 2009 pandemic H1N1 influenza virus reminds us that we are limited in the strategies available to control influenza infection. Vaccines are the best option for the prophylaxis and control of a pandemic; however, the lag time between virus identification and vaccine distribution exceeds 6 months and concerns regarding vaccine safety are a growing issue leading to vaccination refusal. In the short-term, antiviral therapy is vital to control the spread of influenza. However, we are currently limited to four licensed anti-influenza drugs: the neuraminidase inhibitors oseltamivir and zanamivir, and the M2 ion-channel inhibitors amantadine and rimantadine. The value of neuraminidase inhibitors was clearly established during the initial phases of the 2009 pandemic when vaccines were not available, i.e. stockpiles of antivirals are valuable. Unfortunately, as drug-resistant variants continue to emerge naturally and through selective pressure applied by use of antiviral drugs, the efficacy of these drugs declines. Because we cannot predict the strain of influenza virus that will cause the next epidemic or pandemic, it is important that we develop novel anti-influenza drugs with broad reactivity against all strains and subtypes, and consider moving to multiple drug therapy in the future. In this article we review the experimental data on investigational antiviral agents undergoing clinical trials (parenteral zanamivir and peramivir, long-acting neuraminidase inhibitors and the polymerase inhibitor favipiravir [T-705]) and experimental antiviral agents that target either the virus (the haemagglutinin inhibitor cyanovirin-N and thiazolides) or the host (fusion protein inhibitors [DAS181], cyclo-oxygenase-2 inhibitors and peroxisome proliferator-activated receptor agonists).

Figure 1. Sites of action of immunnomodulators and antiviral agents for the control influenza infection

Influenza infects the epithelial cells of the respiratory tract eliciting an immune response characterized by the release of cytokines/chemokines and infiltration of leukocytes. Cox inhibitors and PPAR agonists reduce leukocyte infiltration, presumably by reducing cytokine/chemokine production. Infection is initiated when the virus attaches to sialic acid receptors on the cell surface. This attachment can be inhibited by sialidase inhibitor DAS-181 and hemagglutinin (HA) inhibitor Cyanovirin (CVN). After endocytosis, the pH of the endosome decreases resulting in HA-mediated fusion of the virus and endosomal membranes. Prior to membrane fusion, the M2 ion channel reduces the pH within the virion to allow for release of viral RNA. M2 blockers inhibit the decrease in pH within the virion, thus blocking the release of viral RNA into the cytoplasm. Viral RNA replication occurs in the nucleus and can be blocked by the polymerase inhibitor T-705. Newly made viral mRNA is transported to the cytoplasm where translation of viral proteins occurs. Silencing of specific viral genes can be achieved using small interfering RNAs (siRNA). The maturation of viral proteins such as the viral HA, which occurs in the Golgi, can be disrupted by M2 blockers and Nitazoxanide. Release of mature virions at the cell surface occurs through enzymatic cleavage of sialic acid receptors by the neuraminidase (NA) enzyme. NA inhibitors block NA activity thereby preventing the release of virions from the cell.