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G-quadruplex molecule was found to bind two telomestatin molecules (unpublished 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.