Abstract
Antiviral therapy for AIDS has focused on the discovery and design of inhibitors for two main enzyme targets of the human immunodeficiency virus type 1 (HIV)--reverse transcriptase (RT) and protease (PR). Despite several classes of promising new anti-HIV agents, the clinical emergence of drug-resistant variants of HIV has severely limited the long-term effectiveness of these drugs. Genetic analysis of resistant virus has identified a number of critical mutations in the RT and PR genes. Structural analysis of inhibitor-enzyme complexes and mutational modeling studies are leading to a better understanding of how these drug-resistance mutations exert their effects at a structural level. These insights have implications of the design of new drugs and therapeutic strategies to combat drug resistance to AIDS.
MeSH terms
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Acquired Immunodeficiency Syndrome / drug therapy
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Antiviral Agents / pharmacology*
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Antiviral Agents / therapeutic use
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Drug Design
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Drug Resistance, Microbial / physiology
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Gene Expression Regulation, Enzymologic / drug effects
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Gene Expression Regulation, Enzymologic / genetics
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HIV Protease / chemistry
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HIV Protease / drug effects
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HIV Protease / genetics
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HIV Protease / metabolism
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HIV Protease Inhibitors / chemistry
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HIV Protease Inhibitors / pharmacology*
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HIV Protease Inhibitors / therapeutic use
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HIV Reverse Transcriptase
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HIV-1 / drug effects*
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HIV-1 / genetics
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Humans
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Mutation / drug effects
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Mutation / genetics
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RNA-Directed DNA Polymerase / chemistry
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RNA-Directed DNA Polymerase / genetics
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RNA-Directed DNA Polymerase / metabolism
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Reverse Transcriptase Inhibitors / chemistry
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Reverse Transcriptase Inhibitors / pharmacology*
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Reverse Transcriptase Inhibitors / therapeutic use
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Structure-Activity Relationship
Substances
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Antiviral Agents
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HIV Protease Inhibitors
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Reverse Transcriptase Inhibitors
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HIV Reverse Transcriptase
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RNA-Directed DNA Polymerase
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HIV Protease