Inhibition of HIV-1 replication by combination of a novel inhibitor of TNF-alpha with AZT.
The small molecule S9a was derived from an established tumor necrosis factor-alpha (TNF-alpha) inhibitor (Canventol) by replacement of the isopropylidine group with a phenyl ring. S9a at 10 to 100 nM inhibited HIV production as potently as 3'-azido-3'-deoxythymidine (AZT), an inhibitor of viral reverse transcriptase. Furthermore, S9a and AZT in combination, at noncytoxic concentrations strongly inhibited HIV-1 replication that was more than additive and substantially prolonged the appearance of virus both in acutely infected CD4+ lymphocytes (SupT) in culture and in peripheral blood mononuclear cells (PBMCs) infected with a primary HIV-1 isolate. S9a inhibited TNF-alpha promoter-driven reporter gene activity. It was proposed that the mechanism of antiviral action of S9a was on the host cell, by blocking TNF-alpha transcription via a Tat-induced tar-independent loop, which decreases downstream NF-kappaB activation of HIV-1 long terminal repeat (LTR). S9a was superior to the first generation compound Canventol, which was superior to the natural compound sarcophytol A, demonstrating that further structure-based enhancement of potency of these compounds is feasible. This study suggests a therapeutic approach against AIDS by application of two drugs, one against a cellular and the other a viral target, which may provide an approach to the problem of frequent emergence of resistant variants to combinations of drugs that target only HIV genes.
Division of Cell Growth and Regulation, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA. biswas@mbcrr.harvard.edu
D K
DK
Biswas
A M
AM
Mhashilkar
D S
DS
Ewaniuk
J A
JA
Pezza
L M
LM
Oh
G S
GS
Kannangara
M A
MA
Tius
A B
AB
Pardee
D019380:Anti-HIV Agents / Q000494:pharmacology*; D016588:Anticarcinogenic Agents / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D002460:Cell Line; D003511:Cyclohexanols / Q000737:chemistry / Q000494:pharmacology*; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology; D004338:Drug Combinations; D004357:Drug Synergism; D015696:Gene Products, tat / Q000037:antagonists & inhibitors; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D019169:Jurkat Cells / Q000821:virology; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D012091:Repetitive Sequences, Nucleic Acid / Q000187:drug effects; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects*; D015215:Zidovudine / Q000494:pharmacology*; D054322:tat Gene Products, Human Immunodeficiency Virus
D019380:Anti-HIV Agents; D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D003511:Cyclohexanols; D004224:Diterpenes; D004338:Drug Combinations; D015696:Gene Products, tat; D016328:NF-kappa B; D018894:Reverse Transcriptase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D054322:tat Gene Products, Human Immunodeficiency Virus; C082453:canventol; C058761:sarcophytol A; D015215:Zidovudine