Flexible Nucleosides as Potential Ebola Inhibitors

Abstract

The Ebola pandemic has brought the virus to the forefront of international concern. Ebola’s high capability of evading the body’s immune system is the reason Ebola is extremely virulent. Currently, there is no FDA approved treatment or vaccination for the Ebola virus and with fatality rates fluctuating above 90 percent, a reliable Ebola therapeutic is undeniably necessary. Nucleoside analogues have taken the spotlight as potential antivirals against Ebola; they can function as inhibitors by competing with DNA or RNA, preventing the binding of the natural substrate. Previous studies have shown that inhibiting the enzyme S-adenosylhomocysteine hydrolase (SAHase) has exhibited activity against Ebola. A compound known to inhibit Ebola through SAHase inhibition is the carbocyclic nucleoside 3-deazaneplanocin A (3-deazaNpcA, Fig. 1). My project’s specific aim is to synthesize a flexible version of 3-deazaNpcA, termed Flex-deazaNpcA, where the adenine base of NpcA is replaced by a 3-deazaadenine separated into its imidazole and pyridine moieties, connected by a carbon-carbon bond. We hypothesize that base flexibility modifications will allow for increased beneficial interactions that the stiff adenine base fails to form, all while maintaining the aromatic and hydrogen bonding characteristics of NpcA. This may lead to an enhanced SAHase binder, and therefore a more effective inhibitor.