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 examined 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 laboratory and primary isolates in vitro. In addition, BMT exhibited antiviral activity against SIVmac251. Minimizing energy studies of BMT structure reveal that a trans-disulfide of thiamine (holo drug) disulfide (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-KB (NF-kappa B), resulting in the suppression of HIV-1 replication.
Shoji
S
S
Department of Biochemistry, Faculty of Pharmaceutical Sciences, Kumamoto University, Japan. shoji@gpo.kumamoto-u.ac.jp
Furuishi
K
K
Ogata
A
A
Yamataka
K
K
Tachibana
K
K
Mukai
R
R
Uda
A
A
Harano
K
K
Matsushita
S
S
Misumi
S
S
D000495:Allosteric Site; D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D019556:COS Cells; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D002522:Chlorocebus aethiops; D015696:Gene Products, tat / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000302:isolation & purification / Q000502:physiology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009226:Myristates / Q000737:chemistry / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology; D015302:Simian Immunodeficiency Virus / Q000187:drug effects / Q000502:physiology; D013831:Thiamine / Q000737:chemistry / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects*; D054322:tat Gene Products, Human Immunodeficiency Virus
D019380:Anti-HIV Agents; D015696:Gene Products, tat; D009226:Myristates; D016328:NF-kappa B; C114528:O,O'-bismyristoyl thiamine disulfide; D011355:Prodrugs; D054322:tat Gene Products, Human Immunodeficiency Virus; D013831:Thiamine