Inhibition of human immunodeficiency virus type 1 long terminal repeat-driven transcription by an in vivo metabolite of oltipraz: Implications for antiretroviral therapy Journal Article
| Authors: | Prochaska, H. J.; Fernandes, C. L.; Pantoja, R. M.; Chavan, S. J. |
| Article Title: | Inhibition of human immunodeficiency virus type 1 long terminal repeat-driven transcription by an in vivo metabolite of oltipraz: Implications for antiretroviral therapy |
| Abstract: | Metabolite III (MIII, 7-methyl-6,8-bis(methylthio)pyrrolo[1,2-a]pyrazine), a major in vivo metabolite of oltipraz (OLT, 5-pyrazinyl-4-methyl-1,2-dithiole-3-thione), appears to disrupt human immunodeficiency virus type 1 (HIV-1) replication at a point distal to integration of the viral genome into host DNA. We report that MIII (but not OLT) is a nontoxic inhibitor of long terminal repeat (LTR)-driven expression of β-galactosidase in phorbol-12-myristate-13-acetate (PMA)-stimulated and unstimulated 293.27.2 cells (ED50 = 14 ± 1 and 41 ± 4 μM, respectively). Electrophoretic mobility-shift assays (EMSA) reveal that MIII does not significantly reduce the PMA-induced DNA binding activities of NF-κB or AP-1. Although the mechanism by which MIII inhibits LTR-driven transcription remains unclear, the antiviral synergism of OLT and MIII in vitro are likely due to their independent activities. Whether this translates into antiviral synergy in vivo is being examined by comparing OLT and MIII pharmacokinetics to the pharmacodynamic effects of orally-administered OLT in patients with p24 antigenemia. |
| Keywords: | controlled study; unclassified drug; protein dna binding; transcription factor; drug structure; dna; transcription regulation; gene repression; beta galactosidase; antivirus agent; human immunodeficiency virus; virus replication; drug metabolite; pyrazine derivative; electrophoretic mobility; antiviral activity; human immunodeficiency virus 1; long terminal repeat; phorbol 13 acetate 12 myristate; virus gene; priority journal; article; oltipraz; 7 methyl 6,8 bis(methylthio)pyrrolo[1,2 alpha]pyrazine |
| Journal Title: | Biochemical and Biophysical Research Communications |
| Volume: | 221 |
| Issue: | 3 |
| ISSN: | 0006-291X |
| Publisher: | Elsevier Science, Inc. |
| Date Published: | 1996-04-25 |
| Start Page: | 548 |
| End Page: | 553 |
| Language: | English |
| DOI: | 10.1006/bbrc.1996.0633 |
| PUBMED: | 8629998 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Export Date: 22 November 2017 -- Source: Scopus |
