5′-Phosphonate modified oligoadenylates as potent activators of human RNase L

0552686 - ÚOCHB 2023 RIV GB eng J - Journal Article
Lášek, Tomáš - Petrová, Magdalena - Markusová Kóšiová, Ivana - Šimák, Ondřej - Buděšínský, Miloš - Kozák, Jaroslav - Snášel, Jan - Vavřina, Zdeněk - Birkuš, Gabriel - Rosenberg, Ivan - Páv, Ondřej
5′-Phosphonate modified oligoadenylates as potent activators of human RNase L.
Bioorganic & Medicinal Chemistry. Roč. 56, Feb 15 (2022), č. článku 116632. ISSN 0968-0896. E-ISSN 1464-3391
R&D Projects: GA MŠMT(CZ) EF16_019/0000729
Institutional support: RVO:61388963
Keywords : RNase L * Oligoadenylate * Phosphonate oligonucleotide * OAS-RNase L pathway * 2-5A
OECD category: Biochemistry and molecular biology
Impact factor: 3.5, year: 2022
Method of publishing: Limited access
https://doi.org/10.1016/j.bmc.2022.116632

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.
Permanent Link: http://hdl.handle.net/11104/0327809