Targeting Viral Polymerase

Human Cytomegalovirus (HCMV) infections continue to represent a major health concern in the immunocompromised population, especially recipients of bone marrow and solid-organ transplants. HCMV remains an important cause of congenital viral infection associated with deafness, mental retardation and mortality. Current therapy, which includes ganciclovir (GCV), cidofovir (CDV) and foscarnet (PFA), all suffer from dose-related toxicities, including neutropenia and nephrotoxicity, poor oral bioavailability and the development of drug resistant viral mutants. Nucleosides are small, natural chemical compounds that function as the building blocks of DNA and RNA. Naturally occurring nucleosides are modified in cells to generate derivatives, termed nucleotides, that are utilized by polymerases as the basic building blocks for DNA and RNA. Nucleoside analogs are synthetic compounds that are structurally similar to natural nucleosides. Nucleoside analogs target viral polymerases. Mimicking the role of natural nucleosides, antiviral nucleoside drugs are generally incorporated by viral polymerases into replicating viral genomes. This event impairs either the synthesis or the functionality of the resultant viral genome and therefore suppresses viral replication. Microbiotix has developed a series methylenecyclopropane (MP) compounds, that are purine nucleoside analogues. MP compounds have excellent anti-HCMV activity in vitro and in vivo and are less toxic than ganciclovir. MBX 400, our lead MP compound, interferes with the replication of HCMV inside host cells by targeting the viral polymerase and is effective against all gancicIovir resistant strains tested to date. We have completed Investigational New Drug (IND) enabling preclinical toxicology and safety pharmacology studies.

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