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.
Biswas
D K
DK
Division of Cell Growth and Regulation, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA. biswas@mbcrr.harvard.edu
Mhashilkar
A M
AM
Ewaniuk
D S
DS
Pezza
J A
JA
Oh
L M
LM
Kannangara
G S
GS
Tius
M A
MA
Pardee
A B
AB
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