Substituted naphthalenones as a new structural class of HIV-1 reverse transcriptase inhibitors.
A novel substituted naphthalenone (TGG-II-23A) has been found that inhibits HIV-1 infection of CEM-SS cells at concentrations that are not cytotoxic. Time of addition experiments indicate that TGG-II-23A functions at a stage of the HIV-1 life cycle at or near reverse transcription. Cell free assays confirmed that TGG-II-23A inhibits HIV-1 reverse transcriptase. Similar to other non-nucleoside inhibitors, TGG-II-23A was 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 that of the TIBO-like inhibitors, since a TIBO-resistant HIV-1 was also resistant to TGG-II-23A treatment. TGG-II-23A is a mixed non-competitive inhibitor that exhibits the same template:primer selectivity as other non-nucleoside inhibitors. TGG-II-23A therefore represents a new structural entry into the TIBO/Nevirapine class of inhibitors of HIV-1 reverse transcriptase.
Alam
M
M
Department of Virology, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT 06492-7660.
Bechtold
C M
CM
Patick
A K
AK
Skoog
M T
MT
Gant
T G
TG
Colonno
R J
RJ
Meyers
A I
AI
Li
H
H
Trimble
J
J
Lin
P F
PF
D000998:Antiviral Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology*; D019829:Nevirapine; D010080:Oxazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors; D013601:T-Lymphocytes / Q000166:cytology
D000998:Antiviral Agents; D007093:Imidazoles; D009281:Naphthalenes; D010080:Oxazoles; D011725:Pyridines; D018894:Reverse Transcriptase Inhibitors; D001569:Benzodiazepines; C085140:TGG-II-23A; C067413:R-82913; D019829:Nevirapine; D054303:HIV Reverse Transcriptase