Concepts for the design of anti-HIV nucleoside prodrugs for treating cephalic HIV infection

Abstract

The life cycle of HIV involves nine sequential stages. Of these, the reverse transcription (RT) process is a prime target for drug therapy, using both nucleoside and non-nucleoside inhibitors of RT. There are currently five marketed 2′,3′-dideoxynucleoside RT inhibitors, but there is need for drugs with improved therapeutic efficacy, decreased development of resistance and broader spectrum to treat resistant strains. One approach to improve RT inhibitors is through chemical derivatization using metabolically-cleavable linkages that permit timely regeneration of the active nucleoside inside the body at the site of infection (prodrug formation). Four classes of prodrugs are now reviewed: 2′,3′-dideoxynucleoside masked phosphates, 5′- O-carboxylic acid esters of 2′,3′-dideoxynucleosides, 2′,3′-dideoxycytidine N 4-[(dialkylamino)methylene] prodrugs and 5-halo-6-alkoxy(azido or hydroxy)-5,6-dihydro 2′,3′-dideoxynucleosides. Mutually-masking dual action (MMDA) prodrugs that release a nucleoside RT inhibitor and an abnormal N-myristoyl transferase substrate are presented as a special class of anti-HIV prodrugs that have the potential to interact with the life cycle of the virus at two distinct stages.