Discovery of a small molecule Tat-trans-activation-responsive RNA antagonist that potently inhibits human immunodeficiency virus-1 replication

UMMS Affiliation

Chemical Biology Program, Department of Biochemistry and Molecular Pharmacology

Publication Date


Document Type



Animals; Antiviral Agents; Automation; Carbamates; Cells, Cultured; Chromatography, Gas; Dose-Response Relationship, Drug; Fluorescence Resonance Energy Transfer; Gene Products, tat; HIV-1; Hela Cells; Humans; Ligands; Mice; Models, Biological; Models, Chemical; Models, Statistical; Nucleic Acid Conformation; Oligopeptides; Peptide Library; Protein Binding; RNA; RNA-Directed DNA Polymerase; Structure-Activity Relationship; *Trans-Activation (Genetics); tat Gene Products, Human Immunodeficiency Virus


Life Sciences | Medicine and Health Sciences


Antiretroviral therapy to treat AIDS uses molecules that target the reverse transcriptase and protease enzymes of human immunodeficiency virus, type 1 (HIV-1). A major problem associated with these treatments, however, is the emergence of drug-resistant strains. Thus, there is a compelling need to find drugs against other viral targets. One such target is the interaction between Tat, an HIV-1 regulatory protein essential for viral replication, and trans-activation-responsive (TAR) RNA. Here we describe the design and synthesis of an encoded combinatorial library containing 39,304 unnatural small molecules. Using a rapid high through-put screening technology, we identified 59 compounds. Structure-activity relationship studies led to the synthesis of 19 compounds that bind TAR RNA with high affinities. In the presence of a representative Tat-TAR inhibitor (5 microM TR87), we observed potent and sustained suppression of HIV replication in cultured cells over 24 days. The same concentration of this inhibitor did not exhibit any toxicity in cell cultures or in mice. TR87 was also shown to specifically disrupt Tat-TAR binding in vitro and inhibit Tat-mediated transcriptional activation in vitro and in vivo, providing a strong correlation between its activities and inhibition of HIV-1 replication. These results provide a structural scaffold for further development of new drugs, alone or in combination with other drugs, for treatment of HIV-1-infected individuals. Our results also suggest a general strategy for discovering pharmacophores targeting RNA structures that are essential in progression of other infectious, inflammatory, and genetic diseases.

DOI of Published Version



J Biol Chem. 2003 Oct 3;278(40):39092-103. Epub 2003 Jul 11. Link to article on publisher's site

Journal/Book/Conference Title

The Journal of biological chemistry

Related Resources

Link to Article in PubMed

PubMed ID