Oral manifestation of Herpes simplex virus (HSV-1) infection has frequently been observed in HIV infected patients. Initial treatments with anti viral agents (such as acyclovir for HSV and reverse transcriptase and viral protease inhibitors for HIV-1) have been found to be quite effective. Drug resistance and high sensitivity to multiple drugs, however, often developed in these patients with time. Anti viral strategies aimed at controlling the replication of wild type and mutants of both viruses by drugs which can control both viruses thus are clinically important. Transcription of pro viral HIV and HSV 1E genes (a0, a4, a22, a27, and a47 are essential for replication of these two respective viruses. The expressions are thoroughly host dependent, utilizing RNA polymerase II and cellular transcription factors. The promoter activities of proviral HIV and HSV a4 (ICP4) gene are regulated by host protein Sp1 in addition to other cellular factors. The applicant's laboratory has recently discovered that a plant lignan, 3-0-methyl nordihydroguaiaretic acid (3-0-methyl NDGA, Mal.4) can selectively inhibit HIV proviral transcription and HIV replication by blocking the binding of Sp1 to the Sp1 sites located in HIV promoter. The compound is also effective in inhibition of HIV-1 replication in Hu-PBL-SCID mice. Preliminary experiments have further shown that Mal.4 can inhibit HSV a4 transcription in vitro in a dose-dependent manner in HeLa cell extract.
Specific aims of this proposal are (1) to study the molecular mechanism and its effects underlying the binding of Mal.4 to Sp1 and Sp1 sites in the HIV LTR (2) to examine whether Mal.4 and / or related plant lignans can suppress wild type HSV-1 and recombinant HSV ICP4LACZ in African Green Monkey (VERO) cells,(3) to study the effect of plant lignan in controlling HSV 1 in infected Hu-PBL-SCID mice.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
3R01DE012165-04S1
Application #
6097033
Study Section
Special Emphasis Panel (ZDE1 (31))
Project Start
1996-09-30
Project End
2001-07-31
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Kimura, Kotohiko; Huang, Ru Chih C (2016) Tetra-O-Methyl Nordihydroguaiaretic Acid Broadly Suppresses Cancer Metabolism and Synergistically Induces Strong Anticancer Activity in Combination with Etoposide, Rapamycin and UCN-01. PLoS One 11:e0148685
Huang, Ru Chih C; Chang, Chih Chuan; Mold, David (2006) Survivin-dependent and -independent pathways and the induction of cancer cell death by tetra-O-methyl nordihydroguaiaretic acid. Semin Oncol 33:479-85
Chang, Chih-Chuan; Heller, Jonathan D; Kuo, Jennifer et al. (2004) Tetra-O-methyl nordihydroguaiaretic acid induces growth arrest and cellular apoptosis by inhibiting Cdc2 and survivin expression. Proc Natl Acad Sci U S A 101:13239-44
Huang, Ru Chih C; Li, Yen; Giza, Paul E et al. (2003) Novel antiviral agent tetraglycylated nordihydroguaiaretic acid hydrochloride as a host-dependent viral inhibitor. Antiviral Res 58:57-64
Park, Richard; Giza, Paul E; Mold, David E et al. (2003) Inhibition of HSV-1 replication and reactivation by the mutation-insensitive transcription inhibitor tetra-O-glycyl-nordihydroguaiaretic acid. Antiviral Res 58:35-45
Abd-Elazem, Ibrahim S; Chen, Hong S; Bates, Robert B et al. (2002) Isolation of two highly potent and non-toxic inhibitors of human immunodeficiency virus type 1 (HIV-1) integrase from Salvia miltiorrhiza. Antiviral Res 55:91-106
Heller, J D; Kuo, J; Wu, T C et al. (2001) Tetra-O-methyl nordihydroguaiaretic acid induces G2 arrest in mammalian cells and exhibits tumoricidal activity in vivo. Cancer Res 61:5499-504
Hwu, J R; Tseng, W N; Gnabre, J et al. (1998) Antiviral activities of methylated nordihydroguaiaretic acids. 1. Synthesis, structure identification, and inhibition of tat-regulated HIV transactivation. J Med Chem 41:2994-3000
Chen, H; Teng, L; Li, J N et al. (1998) Antiviral activities of methylated nordihydroguaiaretic acids. 2. Targeting herpes simplex virus replication by the mutation insensitive transcription inhibitor tetra-O-methyl-NDGA. J Med Chem 41:3001-7