ArticleProceedings of the National Academy of Sciences of the United States of America1999
A cytosine analog that confers enhanced potency to antisense oligonucleotides.
Article in Proceedings of the National Academy of Sciences of the United States of America, 1999. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 101 citations in OpenAlex.
- Genetic therapies for neurological diseases.Pharmacological reviews · 2026Review
- Review
- High Affinity Dimeric Uracil-Based Receptor for the Recognition of Adenine Derivatives through Triplex-like Interactions.The Journal of organic chemistry · 2025Article
- Enhancing RNA inhibitory activity using clamp-G-modified nucleobases.Cell reports. Physical science · 2024Article
- Favorable efficacy and reduced acute neurotoxicity by antisense oligonucleotides with 2',4'-BNA/LNA with 9-(aminoethoxy)phenoxazine.Molecular therapy. Nucleic acids · 2024Article
- Structural and Dynamic Features of the Recognition of 8-oxoguanosine Paired with an 8-oxoG-clamp by Human 8-oxoguanine-DNA Glycosylase.Current issues in molecular biology · 2024Article
- Unwinding the SARS-CoV-2 Ribosomal Frameshifting Pseudoknot with LNA and G-Clamp-Modified Phosphorothioate Oligonucleotides Inhibits Viral Replication.Biomolecules · 2023Article
- Article
- Antisense Oligonucleotide Therapy for the Nervous System: From Bench to Bedside with Emphasis on Pediatric Neurology.Pharmaceutics · 2022Review
- The Medicinal Chemistry of Artificial Nucleic Acids and Therapeutic Oligonucleotides.Pharmaceuticals (Basel, Switzerland) · 2022Review
- 2',4'-BNA/LNA with 9-(2-Aminoethoxy)-1,3-diaza-2-oxophenoxazine Efficiently Forms Duplexes and Has Enhanced Enzymatic Resistance*.Chemistry (Weinheim an der Bergstrasse, Germany) · 2021Article
- Cationic oligonucleotide derivatives and conjugates: A favorable approach for enhanced DNA and RNA targeting oligonucleotides.Beilstein journal of organic chemistry · 2021Review
- Fluorescent nucleobases as tools for studying DNA and RNA.Nature chemistry · 2017Review
- A dynamic combinatorial approach for identifying side groups that stabilize DNA-templated supramolecular self-assemblies.International journal of molecular sciences · 2015Article
- Development of new 1,3-diazaphenoxazine derivatives (thioG-grasp) to covalently capture 8-thioguanosine.Molecules (Basel, Switzerland) · 2015Article
- Article
- Fluorescent analogs of biomolecular building blocks: design, properties, and applications.Chemical reviews · 2010Review
- High density labeling of polymerase chain reaction products with the fluorescent base analogue tCo.Analytical chemistry · 2009Article
- RNA major groove modifications improve siRNA stability and biological activity.Nucleic acids research · 2009Article
- Mechanistic studies in the synthesis of a series of thieno-expanded xanthosine and guanosine nucleosides.Tetrahedron · 2008Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Antisense technology is based on the ability to design potent, sequence-specific inhibitors. The G-clamp heterocycle modification, a cytosine analog that clamps on to guanine by forming an additional hydrogen bond, was rationally designed to enhance oligonucleotide/RNA hybrid affinity. A single, context-dependent substitution of a G-clamp heterocycle into a 15-mer phosphorothioate oligodeoxynucleotide (S-ON) targeting the cyclin-dependent kinase inhibitor, p27(kip1), enhanced antisense activity as compared with a previously optimized C5-propynyl-modified p27(kip1) S-ON and functionally replaced 11 C5-propynyl modifications. Dose-dependent, sequence-specific antisense inhibition was observed at nanomolar concentrations of the G-clamp S-ONs. A single nucleotide mismatch between the G-clamp S-ON and the p27(kip1) mRNA reduced the potency of the antisense ON by five-fold. A 2-base-mismatch S-ON eliminated antisense activity, confirming the sequence specificity of G-clamp-modified S-ONs. The G-clamp-substituted p27(kip1) S-ON activated RNase H-mediated cleavage and demonstrated increased in vitro binding affinity for its RNA target compared with conventional 15-mer S-ONs. Furthermore, incorporation of a single G-clamp modification into a previously optimized 20-mer phosphorothioate antisense S-ON targeting c-raf increased the potency of the S-ON 25-fold. The G-clamp heterocycle is a potent, mismatch-sensitive, automated synthesizer-compatible antisense S-ON modification that will have important applications in the elucidation of gene function, the validation of gene targets, and the development of more potent antisense-based pharmaceuticals.
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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.