Small molecule/nucleic acid affinity chromatography: Application for the identification of telomerase inhibitors which target its key RNA/DNA heteroduplex

The purpose of this work is to develop methods for identifying high-affinit y nucleic acid binding species from soluble mixtures of compounds. We have developed and applied an affinity chromatography method for identifying sma ll molecules with high affinity for the telomerase RNA/DNA duplex. An affin ity resin was derivatized with an RNA/DNA duplex which represents the key s tructure that forms during telomerase's catalytic cycle. A soluble mixture of compounds was applied to this resin and the compounds which bound to the highest extent were also confirmed to be the best inhibitors of the enzyme . This correlation of affinity for the RNA/DNA duplex with telomerase inhib ition both supports the duplex as the target of these compounds, and sugges ts that the affinity method may be applied for the identification of higher affinity inhibitors from soluble mixtures of compounds. (C) 2001 Elsevier Science Ltd. All rights reserved.