Selective small molecules blocking HIV-1 Tat and coactivator PCAF association.
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.
Zeng
Lei
L
Structural Biology Program, Department of Physiology and Biophysics, Mount Sinai School of Medicine, New York University, One Gustave L. Levy Place, New York, New York 10029-6574, USA.
Li
Jiaming
J
Muller
Michaela
M
Yan
Sherry
S
Mujtaba
Shiraz
S
Pan
Chongfeng
C
Wang
Zhiyong
Z
Zhou
Ming-Ming
MM
D000123:Acetyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D003959:Diamines / Q000737:chemistry / Q000494:pharmacology*; D015696:Gene Products, tat / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015497:HIV-1 / Q000201:enzymology / Q000378:metabolism*; D051548:Histone Acetyltransferases; D008958:Models, Molecular; D011407:Propane / Q000031:analogs & derivatives* / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D050880:p300-CBP Transcription Factors; D054322:tat Gene Products, Human Immunodeficiency Virus; D000099224:p300-CBP-Associated Factor
D000123:Acetyltransferases; D019380:Anti-HIV Agents; D018797:Cell Cycle Proteins; D003959:Diamines; D015696:Gene Products, tat; D051548:Histone Acetyltransferases; D011407:Propane; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D054322:tat Gene Products, Human Immunodeficiency Virus; D000099224:p300-CBP-Associated Factor