Abstract
Development of drug resistance from mutations in the targeted viral proteins leads to continuation of viral production by chronically infected cells, contributing to HIV-mediated immune dysfunction. Targeting a host cell protein essential for viral reproduction, rather than a viral protein, may minimize the viral drug resistance problem as observed with HIV protease inhibitors. We report here the development of a novel class of N1-aryl-propane-1,3-diamine compounds using a structure-based approach that selectively inhibit the activity of the bromodomain of the human transcriptional co-activator PCAF, of which association with the HIV trans-activator Tat is essential for transcription and replication of the integrated HIV provirus.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Acetyltransferases / antagonists & inhibitors*
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Acetyltransferases / chemistry
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Acetyltransferases / metabolism
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Anti-HIV Agents / chemistry
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Anti-HIV Agents / pharmacology*
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Cell Cycle Proteins / antagonists & inhibitors*
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Cell Cycle Proteins / chemistry
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Cell Cycle Proteins / metabolism
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Diamines / chemistry
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Diamines / pharmacology*
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Gene Products, tat / antagonists & inhibitors*
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Gene Products, tat / chemistry
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Gene Products, tat / metabolism
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HIV-1 / enzymology
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HIV-1 / metabolism*
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Histone Acetyltransferases
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Models, Molecular
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Propane / analogs & derivatives*
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Propane / pharmacology*
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Protein Structure, Tertiary
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Structure-Activity Relationship
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Substrate Specificity
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Transcription Factors / antagonists & inhibitors*
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Transcription Factors / chemistry
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Transcription Factors / metabolism
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p300-CBP Transcription Factors
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tat Gene Products, Human Immunodeficiency Virus
Substances
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Anti-HIV Agents
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Cell Cycle Proteins
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Diamines
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Gene Products, tat
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Transcription Factors
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tat Gene Products, Human Immunodeficiency Virus
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Acetyltransferases
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Histone Acetyltransferases
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p300-CBP Transcription Factors
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p300-CBP-associated factor
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Propane