摘要
HIV-1 integrase （IN）-mediated integration of viral DNA into the host chromosome is an essential step in the virus life cycle. Human lens epithelium-derived growth factor （LEDGF/p75） has been found to function as a cellu- lar cofactor in this process. The LEDGF/p75-1N interaction hence represents an attractive target for anti-HIV ther- apy. In this study, natural products were virtually screened against the LEDGF/p75 binding pocket of HIV-1 IN. 24 compounds were selected and obtained from the National Compound Resource Center of China. AlphaScreen as- says characterized 8 of these 24 natural products as potent LEDGF/p75-IN interaction inhibitors. The active com- pounds whose ICs0 values ranged from 0.56 to 14.55 ~mol/L could be used as lead compounds for further investi- gation. This work confirmed that natural products are valuable resources for antiviral drug discovery.
HIV-1 integrase （IN）-mediated integration of viral DNA into the host chromosome is an essential step in the virus life cycle. Human lens epithelium-derived growth factor （LEDGF/p75） has been found to function as a cellu- lar cofactor in this process. The LEDGF/p75-1N interaction hence represents an attractive target for anti-HIV ther- apy. In this study, natural products were virtually screened against the LEDGF/p75 binding pocket of HIV-1 IN. 24 compounds were selected and obtained from the National Compound Resource Center of China. AlphaScreen as- says characterized 8 of these 24 natural products as potent LEDGF/p75-IN interaction inhibitors. The active com- pounds whose ICs0 values ranged from 0.56 to 14.55 ~mol/L could be used as lead compounds for further investi- gation. This work confirmed that natural products are valuable resources for antiviral drug discovery.
基金
supported by the Program for New Century Excellent Talents in University （No. NCET-08-0774）, the Innovation Program of Shanghai Municipal Education Commission （No. 10ZZ41）, the National Natural Science Foundation of China （No. 21072059）, and the Shanghai Committee of Science and Technology （No. 11DZ2260600）. We thank the National Compound Resource Center for providing compounds. The cDNA coding for HIV IN CCD （residues 50-212） including the F185K solubilizing-mutation was a gift from Prof. Robert Craigie （National Institutes of Health, Bethesda, MD）. The full-length plasmid pCPNat p75 was kindly provided by Prof. Zeger De- byser （Katholieke Universiteit Leuven, Belgium）.
