Durhamycin A, a potent inhibitor of HIV Tat transactivation.
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.
Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, USA. hiranthi_jayasuriya@merck.com
Hiranthi
H
Jayasuriya
Russell B
RB
Lingham
Pia
P
Graham
Donette
D
Quamina
Lucia
L
Herranz
Olga
O
Genilloud
Magda
M
Gagliardi
Renee
R
Danzeisen
Joanne E
JE
Tomassini
Deborah L
DL
Zink
Ziqiang
Z
Guan
Sheo B
SB
Singh
D019380:Anti-HIV Agents / Q000494:pharmacology*; D003364:Costa Rica; D015195:Drug Design; D015967:Gene Expression Regulation, Viral; D015696:Gene Products, tat / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology*; D015497:HIV-1 / Q000502:physiology*; D006868:Hydrolysis; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D015394:Molecular Structure; D008926:Plicamycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D054322:tat Gene Products, Human Immunodeficiency Virus
D019380:Anti-HIV Agents; D015696:Gene Products, tat; C466115:durhamycin A; C466116:durhamycin B; D054322:tat Gene Products, Human Immunodeficiency Virus; D008926:Plicamycin