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.
Identifieur interne : 002453 ( PubMed/Corpus ); précédent : 002452; suivant : 002454Specific 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.
Auteurs : Caterina Fattorusso ; Sandra Gemma ; Stefania Butini ; Paul Huleatt ; Bruno Catalanotti ; Marco Persico ; Meri De Angelis ; Isabella Fiorini ; Vito Nacci ; Anna Ramunno ; Manuela Rodriquez ; Giovanni Greco ; Ettore Novellino ; Alberto Bergamini ; Stefano Marini ; Massimo Coletta ; Giovanni Maga ; Silvio Spadari ; Giuseppe CampianiSource :
- Journal of medicinal chemistry [ 0022-2623 ] ; 2005.
English descriptors
- KwdEn :
- Amino Acid Sequence, Animals, Anti-HIV Agents (chemical synthesis), Anti-HIV Agents (chemistry), Anti-HIV Agents (pharmacology), Binding Sites, Cells, Cultured, Conserved Sequence, Drug Design, Drug Resistance, Viral, Drug Synergism, HIV Reverse Transcriptase (chemistry), HIV-1 (drug effects), HIV-1 (genetics), Humans, Macrophages (drug effects), Macrophages (virology), Mice, Models, Molecular, Mutation, Oxazepines (chemical synthesis), Oxazepines (chemistry), Oxazepines (pharmacology), Pyrroles (chemical synthesis), Pyrroles (chemistry), Pyrroles (pharmacology), Reverse Transcriptase Inhibitors (chemical synthesis), Reverse Transcriptase Inhibitors (chemistry), Reverse Transcriptase Inhibitors (pharmacology), Stereoisomerism, Structure-Activity Relationship, Virus Replication (drug effects), Zidovudine (pharmacology).
- MESH :
- chemical , chemical synthesis : Anti-HIV Agents, Oxazepines, Pyrroles, Reverse Transcriptase Inhibitors.
- chemical , chemistry : Anti-HIV Agents, HIV Reverse Transcriptase, Oxazepines, Pyrroles, Reverse Transcriptase Inhibitors.
- chemical , pharmacology : Anti-HIV Agents, Oxazepines, Pyrroles, Reverse Transcriptase Inhibitors, Zidovudine.
- drug effects : HIV-1, Macrophages, Virus Replication.
- genetics : HIV-1.
- virology : Macrophages.
- Amino Acid Sequence, Animals, Binding Sites, Cells, Cultured, Conserved Sequence, Drug Design, Drug Resistance, Viral, Drug Synergism, Humans, Mice, Models, Molecular, Mutation, Stereoisomerism, Structure-Activity Relationship.
Abstract
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 beta12-beta13 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.
DOI: 10.1021/jm050257d
PubMed: 16279773
Links to Exploration step
pubmed:16279773Le document en format XML
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<term>Anti-HIV Agents (pharmacology)</term>
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<front><div type="abstract" xml:lang="en">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 beta12-beta13 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.</div>
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<Abstract><AbstractText>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 beta12-beta13 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.</AbstractText>
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<ForeName>Caterina</ForeName>
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