Telomestatin, a Potent Telomerase Inhibitor That Interacts Quite Specifically with the Human Telomeric Intramolecular G-Quadruplex

Abstract

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 Each intramolecular G-quadruplex molecule was found to bind two telomestatin molecules (unpublished results).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.

G-Quadruplex stabilization by telomestatin induces TRF2 protein dissociation from telomeres and anaphase bridge formation accompanied by loss of the 3′ telomeric overhang in cancer cells

“…Telomerase activity was significantly inhibited by addition of 5 nM telomestatin ( Figure 1a). These results showed that telomestatin is a potent inhibitor of telomerase activity and were consistent with the previous report (Kim et al, 2002).…”

“…In the BCR-ABL-positive leukemic cell lines OM9;22 and K562, telomestatin inhibits telomerase activity, resulting in telomere shortening and ultimately telomere dysfunction (Tauchi et al, 2003). Telomestatin interacts preferentially with intramolecular versus intermolecular G-quadruplex structures (Kim et al, 2002). Telomestatin is able to stabilize G-quadruplex structures that are formed from duplex human telomeric DNA as well as those formed from single-stranded DNA.…”

Interactions of cryptolepine and neocryptolepine with unusual DNA structures

“…Cryptolepine stabilizes the F21MB quadruplex by 3 °C at 3 µM, whereas the best G4 ligands stabilize by 20 °C or more at 1 µM compound [44]. It is not a potent telomerase inhibitor (IC 50 = 9.4 µM); the best inhibitors described so far have an IC 50 of 50 nM or lower [37,44,[48][49][50].…”

Properties and reactivity of nucleic acids relevant to epigenomics, transcriptomics, and therapeutics

“…A number of distinct chemical mechanisms have emerged for targeting DNA and RNA, but we will only consider the alkylating natural products here. The reader is referred to the reviews [51][52][53] for a comprehensive discussion of the different mechanisms such as non-covalent binders, 54 radical cleavage, 55 reactive oxygen species generation. 56 In the following section we will give an overview of different alkylation strategies that have evolved to target nucleic acids.…”