ArticleACS chemical biology2022
Structure-Guided Design of a Potent and Specific Inhibitor against the Genomic Mutator APOBEC3A.
Article in ACS chemical biology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 23 citations in OpenAlex.
- Deaminase Modulation Driving a New Era in Drug Development.International journal of molecular sciences · 2025Review
- APOBEC3A-Induced DNA Damage Drives Polymerase θ Dependency and Synthetic Lethality in Cancer.bioRxiv : the preprint server for biology · 2025Article
- Next generation APOBEC3 inhibitors: optimally designed for potency and nuclease stability.Nucleic acids research · 2025Article
- Impact of APOBEC3s on the occurrence, development and prognosis of esophageal squamous cell carcinoma.Future oncology (London, England) · 2025Review
- An overview of the functions and mechanisms of APOBEC3A in tumorigenesis.Acta pharmaceutica Sinica. B · 2024Review
- Review
- The cytidine deaminase APOBEC3A regulates nucleolar function to promote cell growth and ribosome biogenesis.PLoS biology · 2024Article
- Targeting APOBECs in cancer: It's about timing.Cancer cell · 2024Article
- Cooperativity between Cas9 and hyperactive AID establishes broad and diversifying mutational footprints in base editors.Nucleic acids research · 2024Article
- APOBEC3A induces DNA gaps through PRIMPOL and confers gap-associated therapeutic vulnerability.Science advances · 2024Article
- Synthesis of 1,4-azaphosphinine nucleosides and evaluation as inhibitors of human cytidine deaminase and APOBEC3A.Beilstein journal of organic chemistry · 2024Article
- Review
- Mutational processes of tobacco smoking and APOBEC activity generate protein-truncating mutations in cancer genomes.Science advances · 2023Article
- Structure-guided inhibition of the cancer DNA-mutating enzyme APOBEC3A.Nature communications · 2023Article
- Seven-membered ring nucleobases as inhibitors of human cytidine deaminase and APOBEC3A.Organic & biomolecular chemistry · 2023Article
- Protein Dynamics and Enzymatic Catalysis.The journal of physical chemistry. B · 2023Review
- Structure-guided inhibition of the cancer DNA-mutating enzyme APOBEC3A.bioRxiv : the preprint server for biology · 2023Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Nucleic acid structure plays a critical role in governing the selectivity of DNA- and RNA-modifying enzymes. In the case of the APOBEC3 family of cytidine deaminases, these enzymes catalyze the conversion of cytosine (C) to uracil (U) in single-stranded DNA, primarily in the context of innate immunity. DNA deamination can also have pathological consequences, accelerating the evolution of viral genomes or, when the host genome is targeted by either APOBEC3A (A3A) or APOBEC3B (A3B), promoting tumor evolution leading to worse patient prognosis and chemotherapeutic resistance. For A3A, nucleic acid secondary structure has emerged as a critical determinant of substrate targeting, with a predilection for DNA that can form stem loop hairpins. Here, we report the development of a specific nanomolar-level, nucleic acid-based inhibitor of A3A. Our strategy relies on embedding the nucleobase 5-methylzebularine, a mechanism-based inhibitor, into a DNA dumbbell structure, which mimics the ideal substrate secondary structure for A3A. Structure-activity relationship studies using a panel of diverse inhibitors reveal a critical role for the stem and position of the inhibitor moiety in achieving potent inhibition. Moreover, we demonstrate that DNA dumbbell inhibitors, but not nonstructured inhibitors, show specificity against A3A relative to the closely related catalytic domain of A3B. Overall, our work demonstrates the feasibility of leveraging secondary structural preferences in inhibitor design, offering a blueprint for further development of modulators of DNA-modifying enzymes and potential therapeutics to circumvent APOBEC-driven viral and tumor evolution.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.