Fluorescence polarization for the evaluation of small-molecule inhibitors of PCAF BRD/Tat-AcK50 association.
A fluorescence polarization competitive assay was developed to efficiently screen and evaluate inhibitors of PCAF bromodomain/Tat-AcK50 protein-peptide interaction. A series of pyridine 1-oxide derivatives were synthesized and evaluated. Some of the novel compounds, 2-(3-aminopropylamino) pyridine 1-oxide derivatives, could be effective inhibitors of PCAF bromodomain/Tat-AcK50 association. Specifically, 2-(3-aminopropylamino)-5-(hydroxymethyl)pyridine 1-oxide hydrochloride (15) and the 5-((3-aminopropylamino)methyl) derivative (20) were found to be effective ligands for the PCAF BRD pocket. First preliminary cellular studies indicate that these small-molecule inhibitors have lower cytotoxicities and are potential leads for the anti-HIV/AIDS therapeutic strategy by targeting host-cell protein PCAF BRD to block HIV replication.
Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Soft Matter Chemistry and Department of Chemistry, University of Science and Technology of China, Hefei, Anhui, 230026 (P.R. China).
Ping
P
Hu
Xinghui
X
Wang
Baiqun
B
Zhang
Shuai
S
Zhang
Qiang
Q
Wang
Zhiyong
Z
Wang
D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005454:Fluorescence Polarization; D015696:Gene Products, tat / Q000737:chemistry / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects* / Q000254:growth & development; D006801:Humans; D008024:Ligands; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects; D050880:p300-CBP Transcription Factors / Q000737:chemistry* / Q000378:metabolism*
D019380:Anti-HIV Agents; D015696:Gene Products, tat; D008024:Ligands; D054852:Small Molecule Libraries; D050880:p300-CBP Transcription Factors
HIV Tat; PCAF; fluorescence polarization; protein-peptide interactions; small-molecule inhibitors