Selective small molecules blocking HIV-1 Tat and coactivator PCAF association

J Am Chem Soc. 2005 Mar 2;127(8):2376-7. doi: 10.1021/ja044885g.

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

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetyltransferases / antagonists & inhibitors*
  • Acetyltransferases / chemistry
  • Acetyltransferases / metabolism
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology*
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / metabolism
  • Diamines / chemistry
  • Diamines / pharmacology*
  • Gene Products, tat / antagonists & inhibitors*
  • Gene Products, tat / chemistry
  • Gene Products, tat / metabolism
  • HIV-1 / enzymology
  • HIV-1 / metabolism*
  • Histone Acetyltransferases
  • Models, Molecular
  • Propane / analogs & derivatives*
  • Propane / pharmacology*
  • Protein Structure, Tertiary
  • Structure-Activity Relationship
  • Substrate Specificity
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / chemistry
  • Transcription Factors / metabolism
  • p300-CBP Transcription Factors
  • tat Gene Products, Human Immunodeficiency Virus

Substances

  • Anti-HIV Agents
  • Cell Cycle Proteins
  • Diamines
  • Gene Products, tat
  • Transcription Factors
  • tat Gene Products, Human Immunodeficiency Virus
  • Acetyltransferases
  • Histone Acetyltransferases
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor
  • Propane