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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