AN ALLOSTERIC DRUG, O,O'-BISMYRISTOYL THIAMINE DISULFIDE, SUPPRESSES HIV-1 REPLICATION THROUGH PREVENTION OF NUCLEAR TRANSLOCATION OF BOTH HIV-1 TAT AND NF-KAPPA-B

The efficacy of o,o'-bismyristoyl thiamine disulfide (BMT) was examine d in detail against HIV-1 laboratory isolates (HTLV-IIIB, JRFL, and MN ), primary isolates (KMT and KMO), and simian immunodeficiency virus ( SIVmac251) in vitro. BMT inhibited the replication of HIV-1 in both la boratory and primary isolates in vitro. In addition, BMT exhibited ant iviral activity against SIVmac251, Minimizing energy studies of BMT st ructure reveal that a trans-disulfide of thiamine (holo drug) disulfid e (TDS, protodrug) is allosterically transited to the reactive twisted disulfide of BMT (allo drug) by o, o'-bismyristoyl esterification of TDS. BMT inhibits nuclear translocation of both HIV-1 transactivator ( Tat) and the cellular transcriptional nuclear factor-kappa B (NF-kappa B), resulting in the suppression of HIV-1 replication. (C) 1998 Acade mic Press.