Inhibition of human immunodeficiency virus (HIV-1/HTLV-IIIBa-L) replication in fresh and cultured human peripheral blood monocytes/macrophages by azidothymidine and related 2',3'-dideoxynucleosides.

Perno, Carlo Federico; Yarchoan, Robert; Cooney, David A.; Hartman, Neil R.; Gartner, Suzanne; Popovič, Mikuláš; Zhang, Hao; Gerrard, Theresa L.; Wilson, Yvonne A.; Johns, David G.

doi:10.1084/jem.168.3.1111

Cited by 226 publications

(115 citation statements)

References 45 publications

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“…Test was conducted as described elsewhere. 33 Macrophages obtained with this method are >95% pure as detected by nonspecific esterase activity. C8166 is a CD4 + T-cell line containing an HTLV-I genome of which only the tat gene is expressed.…”

Section: -(5-bromopyridin-2-yl)-1-(pyrrolo[12-a]quinoxalin-4-yl)semmentioning

confidence: 99%

“…9 The assay to evaluate anti-HIV drug efficacy in acutely infected mature macrophages has been previously described. 33 The antiviral activity of the compounds was assessed by measuring HIV-p24 antigen production in the supernatants of infected cultures as previously described 35 by using a commercially available HIV-antigen kit.…”

Section: -(5-bromopyridin-2-yl)-1-(pyrrolo[12-a]quinoxalin-4-yl)semmentioning

confidence: 99%

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Quinoxalinylethylpyridylthioureas (QXPTs) as Potent Non-Nucleoside HIV-1 Reverse Transcriptase (RT) Inhibitors. Further SAR Studies and Identification of a Novel Orally Bioavailable Hydrazine-Based Antiviral Agent

et al. 2001

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Quinoxalinylethylpyridylthioureas (QXPTs) represent a new class of human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) whose prototype is 6-FQXPT (6). Docking studies based on the three-dimensional structure of RT prompted the synthesis of novel heteroarylethylpyridylthioureas which were tested as anti-HIV agents. Several compounds proved to be potent broad-spectrum enzyme inhibitors and significantly inhibited HIV-1 replication in vitro. Their potency depends on the substituents and the nature of the heterocyclic skeleton linked to the ethyl spacer, and structure-activity relationships are discussed in terms of the possible interaction with the RT binding site. Although the new QXPTs analogues show potent antiviral activity, none of the compounds tested overcome the pharmacokinetic disadvantages inherent to ethylpyridylthioureidic antiviral agents, which in general have very low oral bioavailability. Through an integrated effort involving synthesis, docking studies, and biological and pharmacokinetic evaluation, we investigated the structural dependence of the poor bioavailability and rapid clearance within the thioureidic series of antivirals. Replacing the ethylthioureidic moiety with a hydrazine linker led to a new antiviral lead, offering promising pharmacological and pharmacokinetic properties in terms of antiviral activity and oral bioavailability.

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Section: -(5-bromopyridin-2-yl)-1-(pyrrolo[12-a]quinoxalin-4-yl)semmentioning

confidence: 99%

Section: -(5-bromopyridin-2-yl)-1-(pyrrolo[12-a]quinoxalin-4-yl)semmentioning

confidence: 99%

Quinoxalinylethylpyridylthioureas (QXPTs) as Potent Non-Nucleoside HIV-1 Reverse Transcriptase (RT) Inhibitors. Further SAR Studies and Identification of a Novel Orally Bioavailable Hydrazine-Based Antiviral Agent

et al. 2001

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“…Chemicals toxicity in C8166 was evaluated with a procedure involving a colorimetric assay (MTT assay) that monitors the ability of viable, but not dead, cells to reduce 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) to a blue formazan product, which can be measured spectrophotometrically. 27,28 5. Assay of Antiviral Activity.…”

Section: General Procedures For Preparation Of Compoundsmentioning

confidence: 99%

Specific Targeting Highly Conserved Residues in the HIV-1 Reverse Transcriptase Primer Grip Region. Design, Synthesis, and Biological Evaluation of Novel, Potent, and Broad Spectrum NNRTIs with Antiviral Activity

et al. 2005

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Pyrrolobenzoxazepinones (PBOs) represent a new class of human immunodeficiency virus type 1 (HIV-1) nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) whose prototype is 5. Molecular modeling studies based on the X-ray structures of HIV-1 RT prompted the synthesis of novel analogues which were tested as anti-HIV agents. The PBO derivatives specifically designed to target the highly conserved amino acid residues within the 12-13 hairpin, namely primer grip, proved to be very potent against the most common mutant enzymes, including the highly resistant K103N mutant strain. Structure-activity relationships (SARs) are discussed in terms of a possible interaction with the RT binding site, depending on the nature of the substituents at C-6. Among the pyrrolobenzoxazepines investigated, 15c appeared to be the most promising NNRTI of the series characterized by potent antiviral activity, broad spectrum, and low cytotoxicity. 15c showed synergistic antiviral activity with AZT.

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“…2) (Fig. 4) (4,10,18,23) and then anabolized to 5'-triphosphate (20). This conversion is contingent upon cell division and is severalfold higher in the early exponential growth phase than at the beginning of G2 in the cell cycle (3).…”

Section: Mortalitymentioning

confidence: 99%

“…The objective of this communication is to report the effects of ddC on the hematopoietic system of rabbits given ddC at dosages from 10 to 250 mg/ kg/day for periods up to 18 weeks. Hematopoietic effects were characterized by weekly complete blood counts and by terminal bone marrow histopathologic evaluations.…”

Section: Introductionmentioning

confidence: 99%

Hematological Effects of 2',3'-Dideoxycytidine in Rabbits

et al. 1992

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The antiviral nucleoside analogue 2',3'-dideoxycytidine (ddC) is a DNA chain terminator and/or inhibitor of human immunodeficiency virus (HIV) reverse transcriptase. We evaluated the effects of ddC in 36 New Zealand white rabbits. Three/sex were assigned to a control group and 5 treatment groups (10-250 mg/kg/ day) for 13 or 18 weeks. Blood samples were taken 1 week prior to treatment and weekly thereafter to termination with the exception of the 2 highest dose groups, where blood sample collection was terminated at week 13. Selected hematological analytes were measured weekly with the exception of prothrombin time (PT) and activated partial thromboplastin time (APTT). PT and APTT and selected biochemical analytes were measured prior to treatment, at 7 weeks, and after 13 weeks of treatment. All rabbits were necropsied. Giemsa and hematoxylin and eosin sections were prepared from methacrylate-embedded marrow. Hematological effects included decreases in red blood cell count, hemoglobin, hematocrit, and white blood cell count and increases in mean corpuscular volume and red cell distribution width. Platelets, platelet volume, PT, APTT, and mean corpuscular hemoglobin concentration values were variable or unchanged. Effects were dose-related, most were seen at 1 week, and they persisted to term. Bone marrow histopathologic changes included megalocytosis, erythroid hypoplasia, bizarre erythroid nuclear morphology, nuclear-cytoplasmic asynchrony, and increased mitotic figures. Lymphopenia caused by ddC plateaued at 2 weeks and persisted until termination. Heteropenia (neutropenia) was sporadic. Biochemical values for serum analytes were unchanged by treatment. The principal hematological effect of ddC upon the erythron was characterized as a nonregenerative macrocytic anemia with erythroid hypoplasia and megaloblastic erythropoiesis. We consider the anemia to be of bone marrow origin because of the morphologic changes observed here and produced by the effect of ddC on DNA synthesis in erythroid precursors and/or stromal cells.

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Inhibition of human immunodeficiency virus (HIV-1/HTLV-IIIBa-L) replication in fresh and cultured human peripheral blood monocytes/macrophages by azidothymidine and related 2',3'-dideoxynucleosides.

Cited by 226 publications

References 45 publications

Quinoxalinylethylpyridylthioureas (QXPTs) as Potent Non-Nucleoside HIV-1 Reverse Transcriptase (RT) Inhibitors. Further SAR Studies and Identification of a Novel Orally Bioavailable Hydrazine-Based Antiviral Agent

Quinoxalinylethylpyridylthioureas (QXPTs) as Potent Non-Nucleoside HIV-1 Reverse Transcriptase (RT) Inhibitors. Further SAR Studies and Identification of a Novel Orally Bioavailable Hydrazine-Based Antiviral Agent

Specific Targeting Highly Conserved Residues in the HIV-1 Reverse Transcriptase Primer Grip Region. Design, Synthesis, and Biological Evaluation of Novel, Potent, and Broad Spectrum NNRTIs with Antiviral Activity

Hematological Effects of 2',3'-Dideoxycytidine in Rabbits

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