1. Durhamycin A, a potent inhibitor of HIV Tat transactivation.
- Author
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Jayasuriya H, Lingham RB, Graham P, Quamina D, Herranz L, Genilloud O, Gagliardi M, Danzeisen R, Tomassini JE, Zink DL, Guan Z, and Singh SB
- Subjects
- Costa Rica, Drug Design, Gene Expression Regulation, Viral, Gene Products, tat metabolism, Hydrolysis, Inhibitory Concentration 50, Magnetic Resonance Spectroscopy, Mass Spectrometry, Molecular Structure, Plicamycin pharmacology, Protein Binding drug effects, Structure-Activity Relationship, Substrate Specificity, tat Gene Products, Human Immunodeficiency Virus, Anti-HIV Agents pharmacology, Gene Products, tat antagonists & inhibitors, Gene Products, tat physiology, HIV-1 physiology, Plicamycin analogs & derivatives
- Abstract
Tat is a small HIV protein essential for both viral replication and the progression of HIV disease. In our efforts to discover Tat inhibitors from natural product screening of microbial fermentation extracts, we discovered durhamycin A (1) as a potent inhibitor (IC(50) = 4.8 nM) of Tat transactivation. Detailed NMR and MS/MS studies were utilized to elucidate the structure of 1 as a new member of the aureolic acid family of antibiotics. It consists of tetrasaccharide and disaccharide moieties attached to the aglycone, which is hitherto unknown in the aureolic acid family. Three other novel analogues, durhamycin B (2), compound (3), and the aglycone (4), were also discovered or chemically prepared that were less potent than durhamycin A.
- Published
- 2002
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