INHIBITORS OF PROTEIN-RNA COMPLEXATION THAT TARGET THE RNA - SPECIFICRECOGNITION OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 TAR RNA BY SMALL ORGANIC-MOLECULES

TAR RNA represents an attractive target for the intervention of human immunodeficiency virus type 1 (HIV-1) replication by small molecules. We now describe three small molecule inhibitors of the HIV-1 Tat-TAR i nteraction that target the RNA, not the protein. The chemical structur es and RNA binding characteristics of these inhibitors are unique for each molecule. Results from various biochemical and spectroscopic meth ods reveal that each of the three Tat-TAR inhibitors recognizes a diff erent structural feature at the bulge, lower stem, or loop region of T AR. Furthermore, one of these Tat-TAR inhibitors has been demonstrated , in cellular environments, to inhibit (a) a TAR-dependent, Tat activa ted transcription and (b) the replication of HIV-1 in a latently infec tious model.