Novel antiviral agent tetraglycylated nordihydroguaiaretic acid hydrochloride as a host-dependent viral inhibitor.
A water soluble derivative of nordihydroguaiaretic acid (NDGA), G(4)N (2), synthesized by reaction of NDGA (1) with N,N-dimethylglycine in the presence of dicyclohexylcarbodiimide and dimethylaminopyridine and then with HCl(g) (Scheme 1), competes effectively with the DNA binding domain of recombinant Sp1 protein for binding to the human immunodeficiency virus (HIV) LTR as demonstrated by an electrophoretic mobility-shift assay (EMSA). By blocking Sp1 binding to the HIV LTR, G(4)N suppresses Sp1-regulated HIV Tat transactivation and replication in cultured cells with an IC(50) of 12 microM similar to that of 3'-O-methyl-NDGA as we have previously reported. In addition simian immunodeficiency virus (SIV) replication was completely inhibited by G(4)N at 5.0 microM. G(4)N showed no toxic effect to 174 x CEM cells and H9 cells at 100 microM.
Huang
Ru Chih C
RC
Department of Biology, The Johns Hopkins University, Baltimore, MD 21218, USA. RHUANG@JHU.EDU
Li
Yen
Y
Giza
Paul E
PE
Gnabre
John N
JN
Abd-Elazem
Ibrahim S
IS
King
Ke Yung
KY
Hwu
Jih Ru
JR
D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D019556:COS Cells; D002522:Chlorocebus aethiops; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D024202:Electrophoretic Mobility Shift Assay; D015696:Gene Products, tat / Q000378:metabolism; D016325:HIV Long Terminal Repeat / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D009637:Masoprocol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D015302:Simian Immunodeficiency Virus / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D016329:Sp1 Transcription Factor / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus
D019380:Anti-HIV Agents; D015696:Gene Products, tat; D016329:Sp1 Transcription Factor; D054322:tat Gene Products, Human Immunodeficiency Virus; D009637:Masoprocol