The research project focuses on designing ligands for Tat peptide (25mer) and TAR RNA. The version of Tat peptide under study contains the 10-residue RNA-binding domain from HIV-1 Tat fused to the 15-residue core of EIAV Tat; this peptide displays 15% of the activity of the intact HIV-1 Tat in viral replication in cells. NMR structure analysis and refinement, utilizing some of the complete relaxation matrix methodology we have developed, has lead to the rather highly defined structure of the peptide. Two NMR structures of complexes of Tat fragments with TAR have been published recently. DOCK is being used as one approach to define potential Tat binding agents. The Fine Chemical Database is being screened to find potential ligands for the basic domain of the Tat peptide. Ligands are being designed based on the compounds resulted from the screening with DOCK. The molecular modeling packages ICM and SYBYL are being used to model the interaction of the Tat peptide with the ligands designed The analysis of the results is dependent on the resources of the Computer Graphics Laboratory. In particular, MidasPlus needs to be used for visualization of receptor/ligand complexes.
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