AI Article Synopsis
- - Recent studies have shown that proteins significantly influence how phosphorothioate antisense oligonucleotides (PS-ASOs) are absorbed, distributed, taken up by cells, and how they function or can be toxic.
- - Interactions between PS-ASOs and proteins also affect the behavior of many intracellular proteins, revealing complex relationships that affect drug action and safety.
- - These findings have sparked new research opportunities in medicinal chemistry and molecular pharmacology for PS-ASOs, leading to emerging principles and exciting questions for future studies.
Article Abstract
Recent progress in understanding phosphorothioate antisense oligonucleotide (PS-ASO) interactions with proteins has revealed that proteins play deterministic roles in the absorption, distribution, cellular uptake, subcellular distribution, molecular mechanisms of action, and toxicity of PS-ASOs. Similarly, such interactions can alter the fates of many intracellular proteins. These and other advances have opened new avenues for the medicinal chemistry of PS-ASOs and research on all elements of the molecular pharmacology of these molecules. These advances have recently been reviewed. In this Perspective article, we summarize some of those learnings, the general principles that have emerged, and a few of the exciting new questions that can now be addressed.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1021/jacs.0c04928 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
The Interaction of Phosphorothioate-Containing RNA Targeted Drugs with Proteins Is a Critical Determinant of the Therapeutic Effects of These Agents.
J Am Chem Soc
September 2020
Ionis Pharmaceuticals, Inc., Carlsbad, California 92010-6670, United States.
Recent progress in understanding phosphorothioate antisense oligonucleotide (PS-ASO) interactions with proteins has revealed that proteins play deterministic roles in the absorption, distribution, cellular uptake, subcellular distribution, molecular mechanisms of action, and toxicity of PS-ASOs. Similarly, such interactions can alter the fates of many intracellular proteins. These and other advances have opened new avenues for the medicinal chemistry of PS-ASOs and research on all elements of the molecular pharmacology of these molecules.
View Article and Find Full Text PDFA reappraisal, based on (31)P NMR, of the direct coordination of a metal ion with the phosphoryl oxygen at the cleavage site of a hammerhead ribozyme.
J Am Chem Soc
July 2002
Yamanouchi Pharmaceutical Co. Ltd., 21 Miyukigaoka, Tsukuba Science City 305-8585, Japan.
It has been generally accepted, on the basis of kinetic studies with phosphorothioate-containing substrates and analyses by NMR spectroscopy, that a divalent metal ion interacts directly with the pro-Rp oxygen at the cleavage site in reactions catalyzed by hammerhead ribozymes. However, results of our recent kinetic studies (Zhou, D.-M.
View Article and Find Full Text PDFSynthesis of glucopyranoside-based ligands for D-myo-inositol 1,4,5-trisphosphate receptors.
Carbohydr Res
June 2002
Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, UK.
Adenophostins A and B are naturally occurring glyconucleotides that interact potently with receptors for D-myo-inositol 1,4,5-trisphosphate, an important second messenger molecule in most cell types. Here we describe the design and synthesis of glucopyranoside-based analogues of adenophostin A lacking the adenine component. The key synthetic strategy involves glycosylation of selectively protected alcohols, derived from methyl beta-D-ribofuranoside or 1,4-anhydroerythritol, using glycosyl donors synthesised from 2,6-di-O-benzyl-D-glucopyranose derivatives.
View Article and Find Full Text PDFUsing phosphorothioate-substituted RNA to investigate the thermodynamic role of phosphates in a sequence specific RNA-protein complex.
Biochemistry
January 2000
Department of Chemistry, University of Colorado, Boulder 80309-0215, USA.
Part of the binding affinity and specificity in RNA-protein complexes is often contributed by contacts between the protein and backbone phosphates that are held in position by the RNA structure. This study focuses on the well-characterized interaction between a dimer of the MS2 coat protein and a small RNA hairpin. Using a short oligoribonucleotide which contains all the necessary sequence elements required for tight protein binding, a single phosphorothioate linkage was introduced at 13 different positions.
View Article and Find Full Text PDFInteraction of mRNA with the Escherichia coli ribosome: accessibility of phosphorothioate-containing mRNA bound to ribosomes for iodine cleavage.
Nucleic Acids Res
June 1996
Max-Planck-Institut für Molekulare Genetik, Berlin, Germany.
The contacts of phosphate groups in mRNAs with ribosomes were studied. Two mRNAs were used: one mRNA contained in the middle two defined codons to construct the pre- and the post-translocational states, the other was a sequence around the initiation site of the natural cro-mRNA. Phosphorothioate nucleotides were randomly incorporated at a few A, G, U or C positions during in vitro transcription.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!