Synthesis of Acyclic Flexible Nucleoside Analogues Against Emerging and Reemerging Infectious Diseases.

Abstract

Flaviviruses, such as Dengue (DENV) and Zika (ZIKV) viruses, represent a severe health burden due to their ease of transmission, propensity to become epidemics, and the development of unexpected pathologies. While there are currently no FDA approved treatments or vaccines for these viral diseases, nucleoside analogues have long served as the cornerstone for antiviral therapeutics due to their ability to inhibit viral DNA or RNA replication. However, one of the major issues with the development of antiviral agents against RNA viruses, such as DENV and ZIKV, is the moderately high genetic mutation rate associated with these viruses, which alters the enzymatic binding site and renders the antiviral agents ineffective. One way to potentially overcome this drug resistance is to create a more flexible nucleoside scaffold in order to increase the adaptability and flexibility of the potential drug. In that regard, the Seley-Radtke lab has developed various types of flexible nucleoside analogues called "fleximers" that have demonstrated the ability to overcome point mutations within the binding site of biologically significant enzymes. Preliminary studies have demonstrated that several acyclic flexible analogues of the FDA-approved drug Acyclovir have activity against numerous RNA viruses in vitro, including Middle East Respiratory Syndrome coronavirus (MERS-CoV), Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), Ebola virus (EBOV), DENV and ZIKV, demonstrating their broad-spectrum potential. Furthermore, studies to determine the mechanism of action of the compounds found that the fleximers inhibit DENV and ZIKV methyltransferases (MTases) but not human MTases, making these compounds promising antiviral therapeutics. Furthermore, computational analysis found that, due to their flexibility, these analogues retain interactions necessary for recognition in the viral MTase binding site, but are incompatible in the human MTase binding site. Finally, maximum tolerated dose studies in uninfected mice found that the fleximers were nontoxic up to 250 mg/kg, demonstrating their safety as potential therapeutics. The results of these studies are discussed herein.