Adenovirus can be a significant health risk for immune-compromised patients, both adult and pediatric patients. In pediatric patients in particular, complications associated with adenoviral infection include pneumonia, urinary infections and hepatitis. In the military setting, adenoviruses are endemic in Department of Defense basic recruit training installations and cause frequent epidemics of febrile respiratory disease. An adenovirus vaccine effective against types 4 and 7 is licensed by the FDA, but its future long-term availability is uncertain and there is no vaccine for the prevention of other adenovirus types, including type 14 which has caused fatal respiratory disease in basic recruits as well as in civilian populations. Currently, cidofovir is the only licensed drug that has shown efficacy against adenovirus infections. However, cidofovir can only be given intravenously and its use is further limited due to renal toxicity. Therefore, development and licensure of improved drugs to treat adenovirus infection is of high importance to the public health community. We have developed a platform technology designed to improve the oral absorption of the nucleotide phosphonate drugs, cidofovir (CDV) and HPMPA, such that they will be effective anti-adenoviral oral therapeutic agents. In the phase 1 portion of the project, we propose to synthesize a novel series of CDV and HPMPA prodrugs and evaluate their anti-adenoviral activity against a range of medically relevant adenoviral serotypes. These analogs will also be tested for their pharmacokinetic profile, including absorption and distribution. This work will lay the scientific foundation for development of an effective, oral agent against adenovirus that is implicated in acute respiratory disease and disseminating infection in immune-compromised individuals. For this project, we have established collaborations with Prof. Charles McKenna (analog design and synthesis) at the University of Southern California and Dr. Adriana Kajon (virological studies) at the Lovelace Respiratory Research Institute.
The proposed research addresses a growing medical need in the public health community, namely the increasing incidence of adenoviral infections in pediatric and immunocompromised individuals. In a partnership involving TSRL, Inc., the University of Southern California and Lovelace Respiratory Research Institute, our lead series of promising drug candidates will be examined for in vitro anti-adenoviral activity and in vivo pharmacokinetic properties with the goal of identifying a lead candidate for further preclinical development and, ultimately, clinical evaluation.