INHIBITION OF RNA-POLYMERASE-II TRANSCRIPTION IN HUMAN-CELLS BY SYNTHETIC DNA-BINDING LIGANDS

Sequence-specific DNA-binding small molecules that can permeate human cells potentially could regulate transcription of specific genes. Mult iple cellular DNA-binding transcription factors are required by HIV ty pe 1 for RNA synthesis. Two pyrrole-imidazole polyamides were designed to bind DNA sequences immediately adjacent to binding sites for the t ranscription factors Ets-l, lymphoid-enhancer binding factor 1, and TA TA-box binding protein. These synthetic ligands specifically inhibit D NA-binding of each transcription factor and HIV type 1 transcription i n cell-free assays. When used in combination, the polyamides inhibit v irus replication by >99% in isolated human peripheral blood lymphocyte s, with no detectable cell toxicity, The ability of small molecules to target predetermined DNA sequences located within RNA polymerase II p romoters suggests a general approach for regulation of gene expression , as well as a mechanism for the inhibition of viral replication.