Nucleic acid-binding ligands identify new mechanisms to inhibit telomerase

Bioorg Med Chem Lett. 2004 Jul 5;14(13):3467-71. doi: 10.1016/j.bmcl.2004.04.055.

Abstract

We screened a small library of known nucleic acid-binding ligands in order to identify novel inhibitors of recombinant human telomerase. Inhibitory compounds were classified into two groups: Group I inhibitors had a notably greater effect when added prior to telomerase assemblage and Group II inhibitors displayed comparable inhibition when added before or after telomerase assemblage. Hoechst 33258, a Group I inhibitor, was found to interact tightly (KD = 0.36 microM) with human telomerase RNA (hTR) leading us to propose that hTR is the molecular target for this and other Group I inhibitors. Our results suggest that hTR can be exploited as a small-molecule drug target and provide several new structural motifs for the further development of novel telomerase inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Binding Sites
  • Drug Design
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Ligands
  • Nucleic Acid Conformation
  • Nucleic Acids / chemistry*
  • Nucleic Acids / metabolism
  • RNA / antagonists & inhibitors*
  • RNA / chemistry
  • RNA / metabolism
  • Telomerase / antagonists & inhibitors*
  • Telomerase / chemistry
  • Telomerase / metabolism
  • Telomere / chemistry
  • Telomere / genetics
  • Telomere / metabolism

Substances

  • Enzyme Inhibitors
  • Ligands
  • Nucleic Acids
  • telomerase RNA
  • RNA
  • Telomerase