RNA TARGETS FOR ANTIRETROVIRAL THERAPY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Despite the success of highly active anti-retroviral therapy (HAART), great concern remains due to rapid emergence of new HIV-1 genetic variants that help the virus escape host immunity and multidrug therapies. Hence, the need to develop new anti-HIV therapeutic drugs and search for new targets remains very high. To this end, we have solved a high-resolution NMR structure for an RNA stem-loop structure, SL1, from the 5'-untranslated region of the HIV-1 RNA genome. This structure has a strongly conserved motif, a G-rich internal loop (GRIL), and it is involved in the dimerization of the HIV-1 RNA genome and RNA packaging, two crucial stages of the HIV-1 life cycle. We are using the SL1 NMR structure to carry out a computational screening of small molecules binding SL1. Computational docking is carried out using the MORDOR software, and binding poses are examined using Chimera. Computational hits are verified experimentally using NMR, surface plasmon resonance and fluorescent techniques.