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Development of Small Molecule Inhibitor of
HIV-1 Tat – Protein Phosphatase-1
Interaction as a New Anti-HIV-1 Retroviral
Therapeutics
Kovalskyy, IAS 2007
Sydney
HIV-1 Tat / PP1 interaction
• PP1 is involved in HIV-1 replication cycle
• HIV-1 Tat targets PP1 into nucleus
• NIPP1 inhibits HIV-1 transcription
Ammosova, T., M. et al. J Biol Chem 2003. 278:32189-94
Ammosova, T., M. et al. J Biol Chem 2005. 280:36364-71
Kovalskyy, IAS 2007
Sydney
Target analysis and library design
• Targeting hydrophobic groove at PP1 surface
• Large and flexible molecules
Enaimne Stock
600 000 compounds
Key hydrophobic
interactions
Drug Like Stock*
~300 000 comp
HT Docking
(QXP)
Structure
Filtering
560 comp
Visual inspection
262 compounds
* 280 < MW < 550
Kovalskyy, IAS 2007
Sydney
Results and conclusions
Inhibition and toxicity in CEM-GFP
T-cells and 293T cells
Inhibition of HIV-1
replication
RT, arbitrary counts
600000
500000
400000
300000
200000
100000
0
0
2
4
6
Viral infection, Days
1G3 2uM
1G3 10 uM
1G3 25uM
1H4 2uM
1H4 10 uM
1H4 25 uM
DMSO CTRL
• Proof of concept
• Working inhibitor found
Kovalskyy, IAS 2007
Sydney
8
10
Acknowledgements
ChemBio Center
Howard University
Sergey Nekhai
Tatyana Ammosova
Maxim Platonov
Volodymyr Dubyna
NIAID, NIH
Dr. Kuan Teh-Jeang
Kovalskyy, IAS 2007
Sydney
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