Antimicrobial strategies: inhibition of viral polymerases by 3'-hydroxyl nucleosides

Over the past 20 years, nucleoside analogues have constituted an arsenal of choice in the fight against HIV, hepatitis B and C viruses, and herpesviruses. Classical antiviral nucleosides such as zidovudine act as obligate chain terminators. Once incorporated as monophosphates into the viral nucleic acid, they immediately block the progression of the polymerase as a result of their lack of a reactive 3'-hydroxyl (3'-OH) group. This review explores beyond the paradigm of obligate chain termination, from a structural and a mechanistic perspective, the strategy of inhibiting viral polymerases (RNA- and DNA-dependant) with nucleoside analogues containing a 3'-OH group. Depending on their mechanism of action, these molecules typically fall into the following three categories: (i) delayed chain terminators; (ii) pseudo-obligate chain terminators; or (iii) mutagenic nucleosides. Delayed chain terminators (i.e. penciclovir, cidofovir and entecavir) block the polymerase at an internal position within the viral nucleic acid, whereas R7128 and the 4'C substituted nucleosides do not permit subsequent incorporation events. Ribavirin, 5-hydroxydeoxycytidine and KP1461 are not chain terminators. Instead, they inhibit viral replication after mispairing with the template base, resulting in random mutations that are often lethal. Finally, brivudine, clevudine and other L-nucleosides have unique or yet to be defined mechanisms of inhibition.