A new class of “lock-in”-modified cyclo Sal-pronucleotides has been synthesized. On the example of 5-diacetoxymethyl-cyclo Sal-d4T-monophosphate (5-di-AM-cyclo Sal-d4TMP), the concept of enzymatically activated cyclo Sal-pronucleotides is elucidated. Synthesis, hydrolysis studies, and antiviral activities against HIV are presented.