The NIH has identified a group of infective viruses as ?emerging? because they are a growing threat to public health. This high priority list includes several DNA viruses. Infections with DNA viruses result in significant disease, but few drugs have been approved for this class of pathogens. Cidofovir (CDV, HPMPC) is an acyclic nucleoside phosphonate (ANP) known to exhibit activity against a spectrum of DNA viruses. However, like other ANPs as a class, CDV has significant drawbacks, including inherent lack of oral bioavailability, relatively low potency and nephrotoxicity. Certain novel N-alkyl tyrosinamide prodrugs of CDV and its adenine analog HPMPA recently designed and synthesized by the PI, Professor Charles McKenna at the University of Southern California (USC) exhibit greatly enhanced in vitro potency against CMV and several other DNA viruses relative to the parent drugs and improved selectivity indices. An important virus-dependent variation in potency, selectivity and efficacy enhancement is observed, which has not been explained mechanistically. In this R21 project, these prodrugs and a series of analogs with modified promoiety structures designed to affect activation by phospholipase C will be evaluated for stability and permeability under physiological conditions and for activity against CMV, HSV1, VACV and two emerging DNA viruses: HHV-6B and BK virus. The research will focus on associating individual promoiety structural features with uptake into infected cells and release of drug into the cytoplasm for uptake into viral DNA for each virus, using novel 5-BrHPMPU prodrug derivatives as probes. This information, correlated with the stability, metabolism and in vitro antiviral efficacy data for the five viruses will provide important insights into the mechanism underlying the exceptional but varied potency of this new class of prodrugs with respect to the viruses investigated, while introducing an innovative molecular tool to determine drug promoiety effectiveness. It is also expected to identify new, highly potent compounds for future development into effective therapies for infections by these viruses.
The proposed research addresses the serious threat to public health posed by certain viral pathogens. In a collaboration between the University of Southern California and the University of Alabama at Birmingham, a promising new prodrug platform for enhancing antiviral nucleotide efficacy will be evaluated in vitro against a panel of five DNA viruses, including two ?emerging threat? DNA viruses, using a novel molecular probe to correlate molecular structure and antiviral potency with DNA incorporation. The ultimate goal of this R21 project is to identify rationally designed, more effective and safe antiviral compounds for translation to the clinic.
