SUBSTITUTED NAPHTHALENONES AS A NEW STRUCTURAL CLASS OF HIV-1 REVERSE-TRANSCRIPTASE INHIBITORS

A novel substituted naphthalenone (TGG-II-23A) has been found that inh ibits HIV-1 infection of CEM-SS cells at concentrations that are not c ytotoxic. Time of addition experiments indicate that TGG-II-23A functi ons at a stage of the HIV-1 life cycle at or near reverse transcriptio n. Cell free assays confirmed that TGG-II-23A inhibits HIV-1 reverse t ranscriptase. Similar to other non-nucleoside inhibitors, TGG-II-23A w as specific for HIV-1 and failed to inhibit the replication of HIV-2. The binding site of TGG-II-23A appears to be in close proximity to tha t of the TIBO-like inhibitors, since a TIBO-resistant HIV-1 was also r esistant to TGG-II-23A treatment. TGG-II-23A is a mixed non-competitiv e inhibitor that exhibits the same template:primer selectivity as othe r non-nucleoside inhibitors. TGG-II-23A therefore represents a new str uctural entry into the TIBO/Nevirapine class of inhibitors of HIV-l re verse transcriptase.