Next generation APOBEC3 inhibitors: optimally designed for potency and nuclease stability
Adam K Hedger1,2, Wazo Myint3, Jeong Min Lee1
1Department of Biochemistry and Molecular Biotechnology, UMass Chan Medical School, Worcester, MA 01605, United States.
Nucleic Acids Research
|March 29, 2025
Summary
Researchers developed potent oligonucleotide inhibitors targeting APOBEC3 enzymes (A3A and A3G), crucial in cancer and viral drug resistance. These modified DNA inhibitors show enhanced stability and efficacy, paving the way for new A3-targeted therapies.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- APOBEC3 (A3) enzymes contribute to viral and cancer heterogeneity, often causing drug resistance.
- Current oligonucleotide inhibitors targeting A3 enzymes lack cellular stability and potency.
- Developing effective A3 inhibitors is crucial for therapeutic applications.
Purpose of the Study:
- To enhance the potency and nuclease stability of oligonucleotide inhibitors targeting A3A and A3G enzymes.
- To create novel inhibitors with improved therapeutic potential for A3-mediated diseases.
- To overcome limitations of existing phosphodiester (PO)-linked DNA-based inhibitors.
Main Methods:
- Modification of 2'-deoxyzebularine (dZ) substrate-based oligonucleotide inhibitors.
- Incorporation of phosphorothioate (PS) linkages and mixed PO/PS backbones.
- Introduction of 2'-fluoro sugar modifications and locked nucleic acid (LNA) sugar modifications.
- Design of hairpin-structured inhibitors with optimized PS patterns.
Main Results:
- Mixed PO/PS backbones significantly enhanced inhibitor potency (up to nine-fold) and nuclease resistance.
- Developed the first nanomolar inhibitor of A3G-CTD2 using 2'-fluoro modifications.
- Characterized the first single-digit nanomolar inhibitor of A3A using hairpin structures, optimized PS, and LNA modifications.
- Demonstrated that potent A3A inhibitors restricted A3A deamination in cellulo and were highly nuclease resistant.
Conclusions:
- Optimally designed A3 oligonucleotide inhibitors exhibit superior potency and stability compared to previous agents.
- These enhanced inhibitors represent a significant advancement toward realizing the therapeutic potential of A3 inhibition.
- The developed inhibitors offer a promising strategy for targeting A3 enzymes in viral infections and cancer therapy.
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