Abstract
A series of monopyrrolinone-based HIV-1 protease inhibitors possessing rationally designed P2' side chains have been synthesized and evaluated for activity against wild-type HIV-1 protease. The most potent inhibitor displays subnanomolar potency in vitro for the wild-type HIV-1 protease. Additionally, the monopyrrolinone inhibitors retain potency in cellular assays against clinically significant mutant forms of the virus. X-ray structures of these inhibitors bound in the wild-type enzyme reveal important insights into the observed biological activity.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cattle
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Crystallography, X-Ray
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Drug Design
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HIV Protease / drug effects*
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HIV Protease Inhibitors* / chemical synthesis
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HIV Protease Inhibitors* / chemistry
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HIV Protease Inhibitors* / pharmacology
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Humans
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In Vitro Techniques
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Microbial Sensitivity Tests
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Models, Molecular
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Molecular Conformation
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Mutation
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Pyrrolidinones* / chemical synthesis
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Pyrrolidinones* / chemistry
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Pyrrolidinones* / pharmacology
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Structure-Activity Relationship
Substances
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HIV Protease Inhibitors
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Pyrrolidinones
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HIV Protease