Research Project
6693559
DESCRIPTION (provided by applicant): WEST NILE VIRUS (WNV), a new invader of the US has spread from coast to coast in 2002. As of November 10 (Atlanta Journal Constitution), the total number of WNV cases reported to CDC in 2002 reached 3,529 with 209 deaths in 32 states and Washington D.C. There is no WNV vaccine available. Drugs may be effective against WNV because the infection is typically not chronic. Indeed, identification of active antiviral compounds against a New York isolate of WNV has recently been reported. Among them, mycophenolic acid (MPA) was one of the most potent compounds. However, MPA is not a good candidate for treatment of viral infections due to undesirable metabolic profile. Synthesis of novel analogues of MPA with improved metabolic properties and their evaluation against WNV infections is proposed. Based on our earlier observation that mycophenolic alcohols monophosphates, bis(phosphonates), and mycophenolic adenine dinucleotide (MAD) analogues showed activity against closely related Bovine Viral Diarrhea virus, novel compounds such as phosphonate analogues of MPA and analogues of mycophenolic adenine dinucleotide (MAD) with modified dinucleotide linkages will be synthesized and evaluated against WNV infection. Some phosphonate derivatives are approved antiviral drugs (foscarnet, adefovir, cidofovir). In addition hydroxamic acid analogues of MPA and tetrazole analogues of MPA will be prepared. Hydroxamic acid derivatives are simple, unexplored yet analogues of MPA that are expected to show different physicochemical properties than carboxylic acids (such as MPA) and may show favorable pharmacokinetic. Tetrazole ring can serve as a non-isosteric surrogate for the carboxyl group resulting in "bio-isosteres" that share a variety of biological activities with carboxylic derivatives. The use of tetrazoles in medicinal chemistry is growing fast since these compounds are well transported into cells and often show enhanced activity. These two groups have similar pKa's but different shape and may show improved activity against WNV infection.
