Derivatives of 4-amino-3,6-disulfonato-1,8-naphthalimide inhibit reverse transcriptase and suppress human and feline immunodeficiency virus expression in cultured cells.
We have developed a series of 4-amino-3,6-disulfonato-1,8-naphthalimide (ADSN) derivatives in an attempt to create nontoxic compounds effective against lentivirus infections. The ADSN derivative Lucifer Yellow CH ([N-(hydra zinocarbonyl)amino]-4-amino-3,6-disulfonato-1,8-naphthalimid e) (LYCH) was chosen as a parent compound because of its low toxicity in vivo and in vitro and its tendency to accumulate in monocyte/macrophages, a major reservoir for lentiviruses in vivo. Several ADSN derivatives inhibited reverse transcriptases (RTs) from human immunodeficiency virus type 1 (HIV-1) and feline immunodeficiency virus (FIV). Viral expression in HIV-infected human peripheral blood mononuclear cells was inhibited by noncytotoxic concentrations of two ADSN derivatives, designated A4 (biphenyl-4,4'-dicarboxaldehyde, Lucifer Yellow CH monohydrazone; EC50 = 29 microM after 6 days) and H4 (biphenyl-4,4'-dicarboxaldehyde, Lucifer Yellow CH dihydrazone; EC50 = 5.61 microM). A4 effectively suppressed the expression of FIV in infected Crandall feline kidney fibroblasts (CRFK) at 46.2 microM, reducing the RT levels by 97% after 19 days under conditions allowing direct cell-to-cell transmission of the virus. The viability of drug-treated FIV-infected CRFK cells increased significantly in the presence of A4 relative to the viability of untreated virus-infected cells. In contrast to A4 and H4, LYCH (which lacks the appended aromatic rings characteristic of A4 and H4) had no inhibitory effects on either virus and did not inhibit RT ex vivo. However, flow cytometry studies showed that both A4 and LYCH accumulate in two cell types that can support lentiviral infections: U937 human monocytic leukemic cells that have been induced to differentiate by using tetradecanoyl phorbol acetate, and CRFK cells.
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Department of Molecular Biology, Research Institute of Scripps Clinic, La Jolla, California 92037.
Schinazi
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Pauza
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Lovelace
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Chiang
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Calogeropoulou
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McCarthy
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Elder
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JH
D015057:1-Naphthylamine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002415:Cats; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D004848:Epithelium / Q000187:drug effects / Q000382:microbiology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000382:microbiology; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D016089:Immunodeficiency Virus, Feline / Q000187:drug effects* / Q000502:physiology; D007546:Isoquinolines / Q000494:pharmacology* / Q000633:toxicity; D007668:Kidney; D007963:Leukocytes, Mononuclear / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000187:drug effects / Q000382:microbiology; D009928:Organ Specificity; D018894:Reverse Transcriptase Inhibitors; D013329:Structure-Activity Relationship; D013498:Suramin / Q000494:pharmacology / Q000633:toxicity; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000382:microbiology; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D007546:Isoquinolines; D018894:Reverse Transcriptase Inhibitors; D013498:Suramin; C017475:lucifer yellow; D015057:1-Naphthylamine; D054303:HIV Reverse Transcriptase