Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Development of Small Molecule Inhibitor of HIV
Document related concepts
no text concepts found
Transcript
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
Related documents