title: Bile Acid Conjugated DNA Chimera that Conditionally Inhibits Carbonic Anhydrase-II in the Presence of MicroRNA-21.
abstract: In order to tackle the issue of systemic toxicity in chemotherapy, there is a need to develop novel mechanisms for the activation of protein inhibitors using biomarkers overexpressed in cancer cells. Many current strategies focus on using cancer associated enzymes as a triggering agent for prodrugs. Herein, we detail an alternative approach that harnesses a microRNA (miR-21) that is overexpressed in cancers as the trigger that activates an inhibitor of human carbonic anhydrase-II (hCA-II). Specifically, we have developed a DNA-small molecule chimera (DC) composed of an hCA-II binding lithocholic acid amide (LAA) headgroup that can transition from a rigid duplex state (that does not bind appreciably to hCA) to a single-stranded conformation via a miR-21 trigger. The activated single-stranded DC can project the LAA headgroup into the hCA-II active site and is a robust hCA-II inhibitor (K(i) of 3.12 μM). This work may spur research into developing new classes of cancer selective protein inhibitors.
authors.affiliation: †Department of Chemistry, Tulane University, 2015 Percival Stern Hall, New Orleans, Louisiana 70118, United States.
authors.forename: Xiaozhu
authors.initials: X
authors.lastname: Chu
authors.affiliation: †Department of Chemistry, Tulane University, 2015 Percival Stern Hall, New Orleans, Louisiana 70118, United States.
authors.forename: Cooper H
authors.initials: CH
authors.lastname: Battle
authors.affiliation: †Department of Chemistry, Tulane University, 2015 Percival Stern Hall, New Orleans, Louisiana 70118, United States.
authors.forename: Nan
authors.initials: N
authors.lastname: Zhang
authors.affiliation: †Department of Chemistry, Tulane University, 2015 Percival Stern Hall, New Orleans, Louisiana 70118, United States.
authors.forename: Gyan H
authors.initials: GH
authors.lastname: Aryal
authors.affiliation: ‡RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, Louisiana 70125, United States.
authors.forename: Madhusoodanan
authors.initials: M
authors.lastname: Mottamal
authors.affiliation: †Department of Chemistry, Tulane University, 2015 Percival Stern Hall, New Orleans, Louisiana 70118, United States.
authors.forename: Janarthanan
authors.initials: J
authors.lastname: Jayawickramarajah
mesh_terms: D001647:Bile Acids and Salts / Q000737:chemistry*; D024402:Carbonic Anhydrase II / Q000378:metabolism*; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D020134:Catalytic Domain; D004247:DNA / Q000737:chemistry*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D008958:Models, Molecular; D013329:Structure-Activity Relationship
chemical_list: D001647:Bile Acids and Salts; D002257:Carbonic Anhydrase Inhibitors; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D004247:DNA; D024402:Carbonic Anhydrase II