Abstract
Integrase (IN) represents a clinically validated target for the development of antivirals against human immunodeficiency virus (HIV). Inhibitors with a novel structure core are essential for combating resistance associated with known IN inhibitors (INIs). We have previously disclosed a novel dual inhibitor scaffold of HIV IN and reverse transcriptase (RT). Here we report the complete structure-activity relationship (SAR), molecular modeling, and resistance profile of this inhibitor type on IN inhibition. These studies support an antiviral mechanism of dual inhibition against both IN and RT and validate 3-hydroxypyrimidine-2,4-diones as an IN inhibitor scaffold.
Publication types
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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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Cell Line
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Dose-Response Relationship, Drug
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Drug Design
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Drug Resistance, Viral / genetics
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HIV / drug effects
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HIV / enzymology*
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HIV Integrase / chemistry
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HIV Integrase / genetics
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HIV Integrase / metabolism*
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HIV Integrase Inhibitors / chemical synthesis
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HIV Integrase Inhibitors / chemistry*
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HIV Integrase Inhibitors / pharmacology*
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Hydrophobic and Hydrophilic Interactions
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Models, Molecular
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Mutation
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Protein Conformation
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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry*
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Pyrimidines / pharmacology*
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Structure-Activity Relationship
Substances
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HIV Integrase Inhibitors
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Pyrimidines
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HIV Integrase