The Working Group for Civilian Biodefense has identified orthopox DNA viruses such as variola as a potential bioterrorism threat, and numerous other DNA viruses, including herpes, adeno, pox, polyoma and papilloma viruses, are of general concern in a public health context, as are the possible emergence of new pathogens and the potential for development of drug resistance in existing strains. The development of new compounds effective against a broad spectrum of known and emergent viral pathogens is thus a high priority for NIAID. DNA viruses are not uniform but all have a requirement for DNA synthesis during their life cycle. This essential process therefore remains a key target for antiviral drugs intende to possess broad activity. The acyclic nucleoside phosphonate (ANP) cidofovir (HPMPC) exhibits therapeutically relevant levels of potency against a wide range of DNA viruses. However, the overall usefulness of ANPs and their cyclic forms (CNPs) as antiviral agents has been limited by their inherent lack of bioavailability, which arises from their highly polar phosphonate groups. We have created a general approach to address the lack of oral bioavailability and low cellular permeability of ANP and CNP drugs, based on a novel prodrug strategy that has now led to the development of a promising N-alkyl tyrosinamide prodrug platform. Application of this platform has resulted in prodrugs showing markedly enhanced oral bioavailability, but also significantly greater potency than the parent ANP against several DNA viruses: varicella, cowpox and CMV. In this Phase I SBIR project, we propose to optimize this platform with 4 ANPs and CNPs: HPMPC, HPMPA, cHPMPC and cHPMPA, by synthesizing a series of 20 prodrugs to determine SAR with a set of five diverse DNA viruses. The prodrugs will be tested for compound stability, metabolism, oral absorption and antiviral activity in order to identify lead candidates for preclinical development during the Phase II portion of the project. The proposed program is based upon an established drug research partnership between Dr. John Hilfinger at TSRL, Inc. and Professor Charles McKenna at the University of Southern California and includes Professor Mark Prichard at the University of Alabama at Birmingham as the participating virologist.
The proposed research addresses a potentially catastrophic threat to public health, namely the malicious or accidental introduction of a contagious, potentially lethal viral pathogen into the US population. In a partnership involving TSRL, Inc., and the University of Southern California, a set of novel nucleotide derivatives will be synthesized and investigated for antiviral effect against a broad range of viral pathogens. Promising drug candidates showing highly potent in vitro antiviral activity and low cytotoxicity will be examined for oral availability with the goal of identifying a lead series of compounds for further preclinical development and ultimately, clinical evaluation.
| Krylov, Ivan S; Kashemirov, Boris A; Hilfinger, John M et al. (2013) Evolution of an amino acid based prodrug approach: stay tuned. Mol Pharm 10:445-58 |
