Filoviruses, coronaviruses, and flaviviruses are the cause of diseases with high mortality rates and currently there are no FDA approved drugs for treatment. One potential treatment option is nucleoside analogues, which are known to inhibit viral replication thus making them a promising therapy. Unfortunately, the appearance of drug resistant viruses rapidly outmodes new medicines. To combat these viruses, the Seley-Radtke lab has pioneered the development of nucleoside fleximers – molecules capable of overcoming viral point mutations due to flexibility in the nucleobase scaffold.
This lab has previously discovered nucleoside fleximers based on the structure of the FDA-approved analogue Acyclovir that demonstrate broad spectrum in vitro activity against filoviruses, coronaviruses, and flaviviruses. The first half of this project seeks to produce a supply of these compounds adequate for in vivo studies, specifically animal and pharmacokinetic studies. The second half of this project is the synthesis of two novel fleximers. These novel fleximers are similar in structure to compounds with established in vitro activity, and the testing of these compounds in a mini-structure activity relationship study will help elucidate more information on the binding site of the highly conserved flavivirus enzyme, methyltransferase.