5'-Phosphonate modified oligoadenylates as potent activators of human RNase L
Language English Country Great Britain, England Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
35078032
DOI
10.1016/j.bmc.2022.116632
PII: S0968-0896(22)00024-4
Knihovny.cz E-resources
- Keywords
- 2-5A, OAS-RNase L pathway, Oligoadenylate, Phosphonate oligonucleotide, RNase L,
- MeSH
- Adenine Nucleotides chemical synthesis chemistry pharmacology MeSH
- Endoribonucleases metabolism MeSH
- Nucleic Acid Conformation MeSH
- Humans MeSH
- Oligoribonucleotides chemical synthesis chemistry pharmacology MeSH
- Organophosphonates chemical synthesis chemistry pharmacology MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- 2-5A-dependent ribonuclease MeSH Browser
- 2',5'-oligoadenylate MeSH Browser
- Adenine Nucleotides MeSH
- Endoribonucleases MeSH
- Oligoribonucleotides MeSH
- Organophosphonates MeSH
The oligoadenylate synthetase-ribonuclease L pathway is a major player in the interferon-induced antiviral defense mechanism of cells. Upon sensing viral dsRNA, 5'-phosphorylated 2',5'-oligoadenylates are synthesized, and subsequently activate latent RNase L. To determine the influence of 5'-phosphate end on the activation of human RNase L, four sets of 5'-phosphonate modified oligoadenylates were prepared on solid-phase. The ability of these 5'-modified oligoadenylates bearing shortened, isosteric and prolonged phosphonate linkages to activate RNase L was explored. We found that isosteric linkages and linkages prolonged by one atom were in general well tolerated by the enzyme with the EC50 values comparable to that of the natural activator. In contrast, linkages shortened by one atom or prolonged by two atoms exhibited decrease in the activity.
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