Charles E McKenna
University of Southern California, USA
Title: Prodrugs as a Strategy for More Effective Anti-Adenovirus Agents
Biography
Biography: Charles E McKenna
Abstract
Human adenoviruses (AdV) cause generally mild infections of the respiratory and GI tracts as well as some other tissues. However, certain serotypes are associated with acute respiratory disease and epidemic keratoconjunctivitis. AdV can cause serious infection in severely immunosuppressed individuals, and pediatric patients undergoing allogeneic hematopoietic stem cell transplantation have mortality rates up to 80% with disseminated disease. Despite this significant challenge to health, there are no drugs approved specifically to treat AdV infections. Cidofovir, an analog of cytidine monophosphate which acts as an AdV DNA chain terminator, is used clinically, but has several drawbacks, including relatively low cellular potency and lack of oral bioavailability. USC-087, a novel N-alkyl tyrosinamide phosphonate ester prodrug of HPMPA, the adenine analogue of cidofovir, is markedly more potent than the parent drug or cidofovir itself against multiple AdV types in cell culture. USC-087 is also effective orally against AdV-C6 in a cyclophosphamide immunosuppressed permissive Syrian hamster model. Injection of AdV-C6 (or AdV-C5) intravenously leads to a disseminated infection that resembles the human disease. USC-087 completely prevented or significantly decreased mortality when administered orally up to 4 days post challenge with the median lethal intravenous dose of AdV-C6. USC-087 also prevented or significantly decreased liver damage caused by AdV-C6 infection, and suppressed virus replication up to 4 days post challenge. The potential and scope of the N‑alkyl tyrosinamide ester prodrug approach will be discussed.