No abstract

TAR RNA is a potential target for AIDS therapy. Ligand-based virtual screening was performed to retrieve novel scaffolds for RNA-binding molecules capable of inhibiting the Tat-TAR interaction, which is essential for HIV replication. We used a "fuzzy" pharmacophore approach (SQUID) and an alignment-free pharmacophore method (CATS3D) to carry out virtual screening of a vendor database of small molecules and to perform "scaffold-hopping". A small subset of 19 candidate molecules were experimentally tested for TAR RNA binding in a fluorescence resonance energy transfer (FRET) assay. Both methods retrieved molecules that exhibited activities comparable to those of the reference molecules acetylpromazine and chlorpromazine, with the best molecule showing ten times better binding behavior (IC50 = 46 microM). The hits had molecular scaffolds different from those of the reference molecules.

Sticking to TAR: The development of RNA‐binding drugs will open fascinating opportunities for modern pharmacology. Experience in how to find ligands for RNA targets, however, is still limited. Lessons learnt from well‐characterized RNA–protein complexes such as tat/TAR, therefore, will significantly contribute to the future development of the field. TAR RNA, the trans‐activation responsive region of HIV, and the tat protein form a molecular switch crucial for viral replication. Herein we review the state of research concerning TAR‐binding molecules and the techniques used to study RNA–ligand association.

Organic chemistryOrganic chemistry Z 0200Targeting the HIV trans-Activation Responsive Region -Approaches Towards RNA-Binding Drugs -[43 refs.]. -(KREBS, A.; LUDWIG, V.; BODEN, O.; GOEBEL*, M. W.; ChemBioChem 4 (2003) 10, 972-978; Inst. Org. Chem., Johann Wolfgang Goethe-Univ., D-60439 Frankfurt/M., Germany; Eng.) -Lindner 49-258