Nucleic acid-binding ligands identify new mechanisms to inhibit telomerase.
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.
Dominick
Pamela K
PK
School of Pharmacy, Division of Medicinal Chemistry and Natural Products, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7360, USA.
Keppler
Brian R
BR
Legassie
Jason D
JD
Moon
Ian K
IK
Jarstfer
Michael B
MB
D001483:Base Sequence; D001665:Binding Sites; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D009690:Nucleic Acid Conformation; D009696:Nucleic Acids / Q000737:chemistry* / Q000378:metabolism; D012313:RNA / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D016615:Telomere / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D004791:Enzyme Inhibitors; D008024:Ligands; D009696:Nucleic Acids; C422952:telomerase RNA; D012313:RNA; D019098:Telomerase