Abstract
The design, synthesis, and biological evaluation of novel C3-substituted cyclopentyltetrahydrofuranyl (Cp-THF)-derived HIV-1 protease inhibitors are described. Various C3-functional groups on the Cp-THF ligand were investigated in order to maximize the ligand-binding site interactions in the flap region of the protease. Inhibitors 3c and 3d have displayed the most potent enzyme inhibitory and antiviral activity. Both inhibitors have maintained impressive activity against a panel of multidrug resistant HIV-1 variants. A high-resolution X-ray crystal structure of 3c-bound HIV-1 protease revealed a number of important molecular insights into the ligand-binding site interactions.
Copyright © 2012 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Binding Sites
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Crystallography, X-Ray
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Cyclopentanes / chemical synthesis*
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Cyclopentanes / pharmacology
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Darunavir
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Drug Design
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Drug Resistance, Viral / drug effects
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Furans / chemical synthesis*
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Furans / pharmacology
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HIV Protease / metabolism*
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HIV Protease Inhibitors / chemical synthesis*
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HIV Protease Inhibitors / pharmacology
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HIV-1 / drug effects
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HIV-1 / enzymology
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Humans
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Leukocytes, Mononuclear / drug effects
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Leukocytes, Mononuclear / virology
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Models, Molecular
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Stereoisomerism
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Structure-Activity Relationship
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Sulfonamides / pharmacology
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Urethane / analogs & derivatives*
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Urethane / chemical synthesis*
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Urethane / pharmacology
Substances
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Cyclopentanes
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Furans
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HIV Protease Inhibitors
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Sulfonamides
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Urethane
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HIV Protease
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p16 protease, Human immunodeficiency virus 1
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Darunavir