PNA-based RNA-triggered drug-releasing system.
A three-component sequence-specific RNA-triggered drug-releasing system is described that consists of an 8-mer PNA linked to a coumarin ester (the prodrug component) and a 14-mer PNA linked to histidine (the catalytic component) that are complementary to the C loop of E. coli 5S rRNA (the triggering component). Binding of the catalytic component to the RNA creates a prodrug-metabolizing enzyme that catalyzes a 60,000-fold acceleration in the rate of coumarin release from the prodrug compared to the rate of coumarin release from the ester subunit catalyzed by imidazole alone. RNA-triggered release of hydroxycoumarin is only slightly less efficient than that triggered by a short unfolded DNA sequence corresponding to the PNA binding sites. The lower efficiency results from a decrease in k(cat) and an increase in K(M), presumably due to the bent nature of the RNA. The efficiency of DNA-triggered hydroxycoumarin release was found to depend on the distance between the catalytic and prodrug components.
Ma
Zhaochun
Z
Department of Chemistry, Washington University, St. Louis, Missouri 63130, USA.
Taylor
John-Stephen
JS
D015110:4-Hydroxycoumarins / Q000493:pharmacokinetics; D016503:Drug Delivery Systems / Q000379:methods*; D009690:Nucleic Acid Conformation; D020135:Peptide Nucleic Acids / Q000138:chemical synthesis / Q000235:genetics / Q000493:pharmacokinetics*; D011355:Prodrugs / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D012313:RNA / Q000737:chemistry / Q000235:genetics / Q000493:pharmacokinetics*
D015110:4-Hydroxycoumarins; D020135:Peptide Nucleic Acids; D011355:Prodrugs; D012313:RNA; C068805:4-hydroxycoumarin