“…For many decades, nucleoside analogues have been applied in antiviral and antitumoral chemotherapy and they still comprise the frontline of drugs used to combat infections caused by HIV, herpes virus, and hepatitis B and C viruses. , The antiviral efficacy of many nucleoside analogues such as 3′-deoxy-2′,3′-dehydrothymidine (d4T, 1 ; Scheme ) or 3′-deoxy-3′-azidothymidine (AZT) are strongly dependent on their intracellular activation by host cell kinases to give, via the monophosphate ( 2 , NMP) and the diphosphate ( 3 , NDP), ultimately the bioactive nucleoside analogue triphosphate derivatives ( 4 , NTP). , The targets of effective nucleoside analogue drugs are the virus-encoded DNA or RNA polymerases, such as the HIV reverse transcriptase (RT) , or the HCV-encoded RNA-dependent RNA-polymerase NS5B, which are the key enzymes in the replication cycle of HIV and HCV, respectively. Up to now, many nucleoside analogues have been approved as HIV-RT inhibitors (NRTIs) and they are used as the backbone of the combined antiretroviral therapy (cART) . However, cellular kinases often catalyze these biotransformations insufficiently, resulting in low or no biological activity of the given compound. ,, Moreover, the clinical efficacy of nucleoside analogues is hampered by limitations such as poor biological half-lives due to catabolic elimination from the body, mutations of nucleoside transporters, variable bioavailability after oral administration, or development of drug resistance. − These hurdles can be overcome by using lipophilic prodrugs of the phosphorylated parent nucleosides, which are able to bypass the rate-limiting, kinase-catalyzed conversion steps, such as tenofovir and sofosbuvir. , In the past, this task has been successfully achieved for the intracellular delivery of NMP using prodrug strategies − such as the cyclo Sal-, − SATE-, , bisPOM-, or phosphoramidate nucleotides. , …”