Targeting telomerase via its key RNA/DNA heteroduplex

Telomerase is a promising "universal" anticancer target. It has been demons trated that inhibition of telomerase leads to mortalization and death of pr eviously immortal cell lines. We are interested in targeting telomerase by binding to the RNA/DNA duplex that forms during its catalytic cycle. The RN A strand of this duplex is a component of telomerase and acts as a template to direct the synthesis of the single-stranded DNA telomere. We have hypot hesized that molecules that bind to this duplex will inhibit the enzyme by either preventing strand dissociation or by sufficiently distorting the sub strate, thereby causing a misalignment of key catalytic residues. To test t his hypothesis: we have examined the activity of telomerase in the presence of a range of intercalating molecules, known for their broad duplex bindin g properties. Of the nine compounds we examined, four show promising lead a ctivity in the low micromolar range. A kinetic analysis of the telomeric pr oducts suggests that these compounds do not act by stabilizing G-quartets. thereby supporting the telomeric RNA/DNA heteroduplex as the rite of action . We anticipate using these lead compounds as the basis for combinatorial v ariation to increase the affinity acid specificity for the target telomeras e. (C) 2001 Academic Press.