Targeting Viral Entry

The first step of a productive viral infection requires the binding of viral envelope proteins to specific cell surface receptors. This selective association between viral envelope proteins is a multistep process and requires highly specific sequential engagements between the viral envelope proteins and specific cell surface receptors and/or coreceptors. Blocking viral entry into the target cell leads to suppression of viral infectivity, replication and the cytotoxicity induced by virus-cell interaction.

Hepatitis C Virus (HCV) is recognized as a worldwide health problem affecting over 170 million people. HCV causes a spectrum of diseases ranging from an asymptomatic carrier state to end-stage liver disease, which includes cirrhosis and hepatocellular carcinoma. A vaccine for HCV is currently not available. The present therapies for HCV infection rarely result in viral clearance, are difficult to administer and cause serious toxic side effects. There are several drugs that have been developed and are under trial for HCV infection. These drugs target the HCV-encoded serine protease (NS3) and RNA polymerase (NS5B) that have emerged as favorite targets in the race for new anti-HCV drugs. Microbiotix has an active program to develop entry inhibitors against HCV. However, unlike others, we are targeting the viral entry process by attacking the selective interaction between viral envelope glycoproteins and specific cell-surface receptor(s). Since this virus is difficult to culture in vitro we have generated pseudotype virus expressing HCV envelope glycoproteins as a surrogate model to screen for inhibitors that target the viral entry process. HCV, like HIV, has a high mutation rate and therefore there will be high probability for the emergence of drug-resistant virus. Combination therapy, either with the existing treatments or with other specific antiviral drugs, will be needed to control the virus — a point that underscores the importance of continuing to develop inhibitors against various viral targets. Therefore, the development of this entirely new class of inhibitors will have enormous impact on the treatment and management of chronic HCV infection. Furthermore, the FDA approval of the HIV fusion inhibitor T20 (enfuvirtide/Fuzeon Ò) demonstrates the clinical feasibility of this antiviral approach.

Recent outbreaks of highly pathogenic avian influenza A (H5N1) infections in poultry and in humans (through direct contact with infected birds) have highlighted the need to develop new anti-influenza therapeutics that will be active against all subtypes of this infection, including a newly emerged pandemic strain. Vaccines, the main strategy for protection against influenza epidemics, will not be effective against emerging strains not present in the vaccine. The currently available anti-influenza drugs, viral M2 ion-channel inhibitors (amantadine and its derivatives) and neuraminidase (NA) inhibitors (oseltamivir and zanamivir) have experienced limited success because of their strain specificity and emergence of drug resistance strains. We are developing new anti-influenza therapeutics that target the highly conserved fusion and receptor binding domain of the envelope protein hemagglutinin (HA). A novel inhibitor targeting either of the conserved sites should be active against multiple subtypes, including a newly emerged pandemic strain. For drug discovery, we have generated a pseudotype virus expressing HA from the pandemic H5N1 strain, as a surrogate model, to mimic HA-mediated entry. This surrogate model system is being used to screen for inhibitors against the HA of pathogenic avian influenza A (H5N1) virus under BSL2 conditions.