Bile Acid Conjugated DNA Chimera that Conditionally Inhibits Carbonic Anhydrase-II in the Presence of MicroRNA-21
Xiaozhu Chu1, Cooper H Battle1, Nan Zhang1
1†Department of Chemistry, Tulane University, 2015 Percival Stern Hall, New Orleans, Louisiana 70118, United States.
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.
Insights
Researchers developed a novel cancer-targeting drug delivery system. This system uses microRNA-21 (miR-21) to activate a protein inhibitor, offering a new strategy for cancer therapy with reduced systemic toxicity.
Area of Science:
- Biochemistry
- Molecular Biology
- Medicinal Chemistry
Background:
- Systemic toxicity from chemotherapy necessitates novel drug activation mechanisms.
- Current strategies often rely on cancer-specific enzymes to trigger prodrugs.
- MicroRNAs (miRs) overexpressed in cancer present an alternative biomarker for targeted drug activation.
Purpose of the Study:
- To develop a novel cancer-selective protein inhibitor activated by microRNA-21 (miR-21).
- To create a DNA-small molecule chimera (DC) that targets human carbonic anhydrase-II (hCA-II).
- To explore miR-21 as a trigger for activating protein inhibitors.
Main Methods:
- Designed a DNA-small molecule chimera (DC) with a lithocholic acid amide (LAA) headgroup.
- Utilized miR-21 as a trigger to transition the DC from a duplex to a single-stranded state.
- Assessed the inhibitory activity of the activated DC against hCA-II.
Main Results:
- The DNA-small molecule chimera (DC) transitions to an active single-stranded form upon binding miR-21.
- The activated DC effectively inhibits human carbonic anhydrase-II (hCA-II).
- Achieved a robust inhibition constant (K(i)) of 3.12 μM for hCA-II.
Conclusions:
- A novel miR-21-activated inhibitor of hCA-II was successfully developed.
- This approach offers a new paradigm for cancer-selective protein inhibitor design.
- The findings may inspire new classes of targeted cancer therapeutics.
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