Telomestatin, a potent telomerase inhibitor that interacts quite specifically with the human telomeric intramolecular g-quadruplex

J Am Chem Soc. 2002 Mar 13;124(10):2098-9. doi: 10.1021/ja017308q.


Telomestatin is a natural product isolated from Streptomyces anulatus 3533-SV4 and has been shown to be a very potent telomerase inhibitor. The structural similarity between telomestatin and a G-tetrad suggested to us that the telomerase inhibition might be due to its ability either to facilitate the formation of or trap out preformed G-quadruplex structures, and thereby sequester single-stranded d[T(2)AG(3)](n) primer molecules required for telomerase activity. Significantly, telomestatin appears to be a more potent inhibitor of telomerase (5 nM) than any of the previously described G-quadruplex-interactive molecules. In this communication we provide the first experimental evidence that telomestatin selectively facilitates the formation of or stabilizes intramolecular G-quadruplexes, in particular, that produced from the human telomeric sequence d[T(2)AG(3)](4). A simulated annealing (SA) docking approach was used to study the binding interactions of telomestatin with the intramolecular antiparallel G-quadruplex structure. Each intramolecular G-quadruplex molecule was found to bind two telomestatin molecules (unpublished results). A 2:1 model for the telomestatin bound in the external stacking mode in an energy minimized complex with the human telomeric basket-type G-quadruplex was constructed. Our observation that a G-quadruplex-interactive molecule without significant groove interactions is able to reorient in a G-quadruplex structure proints to the importance of core interaction with an asymmetric G-quadruplex structure in producing selective binding. Furthermore, the G-quadruplex interactions of telomestatin are more selective for the intramolecular structure in contrast to other G-quadruplex-interactive agents, such as TMPyP4.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • DNA / chemistry*
  • DNA / drug effects
  • DNA / metabolism
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Guanine / chemistry
  • Guanine / metabolism
  • Humans
  • Models, Molecular
  • Nucleic Acid Conformation / drug effects
  • Oxazoles / chemistry
  • Oxazoles / pharmacology*
  • Repetitive Sequences, Nucleic Acid
  • Substrate Specificity
  • Telomerase / antagonists & inhibitors*


  • Enzyme Inhibitors
  • Oxazoles
  • telomestatin
  • Guanine
  • DNA
  • Telomerase