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Activation of murine RNase L by isopolar 2'-phosphonate analogues of 2',5' oligoadenylates
Pav O., Protivinska E., Pressova M., Collinsova M., Jiracek J., Snasel J., Masojidkova M., Budesinsky M., Rosenberg I.
Jazyk angličtina Země Spojené státy americké
Typ dokumentu techniky in vitro
- MeSH
- adeninnukleotidy farmakologie chemická syntéza chemie MeSH
- endoribonukleasy metabolismus MeSH
- financování organizované MeSH
- myši inbrední BALB C MeSH
- myši MeSH
- oligoribonukleotidy farmakologie chemická syntéza chemie MeSH
- organofosfonáty farmakologie chemická syntéza chemie MeSH
- slezina enzymologie MeSH
- stereoizomerie MeSH
- vazba proteinů MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- techniky in vitro MeSH
To determine the influence of methylene group insertion in the internucleotide linkage on the binding process of 2',5'-oligoadenylates to RNase L, a series of 2'-phosphonate-modified trimers and tetramers were synthesized from appropriate monomeric units and evaluated for their ability to bind to murine RNase L. Tetramers pAAXA modified by ribo-, arabino-, or xylo-2'-phosphonate unit X in the third position were capable of binding to RNase L in nanomolar concentrations. The replacement of the first residue (pXAAA), or both the first and the third residues (pXAXA), was also tolerated by the enzyme. In contrast, in all cases, the replacement of the second residue (pAXAA) resulted in the significant decrease of binding ability. Additionally, no more than two phosphonate modifications in the tetramer were allowed to retain the binding affinity to the enzyme. Although all three tetramers pAAXA were found to be potent enzyme binders, only tetramers modified by ribo- and xylo-2'-phosphonate unit X activated the RNase L-catalyzed cleavage of the RNA substrate. Surprisingly, tetramer pAAXA, modified by arabino-2'-phosphonate unit X, did not activate the enzyme and can be considered a potent antagonist. In comparison with their natural counterpart, the phosphonate analogues of the pA4 exhibit superior resistance toward nucleases present in the murine spleen homogenate.
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- $a Activation of murine RNase L by isopolar 2'-phosphonate analogues of 2',5' oligoadenylates / $c Pav O., Protivinska E., Pressova M., Collinsova M., Jiracek J., Snasel J., Masojidkova M., Budesinsky M., Rosenberg I.
- 314 __
- $a Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, 166 10 Prague 6, Czech Republic
- 520 9_
- $a To determine the influence of methylene group insertion in the internucleotide linkage on the binding process of 2',5'-oligoadenylates to RNase L, a series of 2'-phosphonate-modified trimers and tetramers were synthesized from appropriate monomeric units and evaluated for their ability to bind to murine RNase L. Tetramers pAAXA modified by ribo-, arabino-, or xylo-2'-phosphonate unit X in the third position were capable of binding to RNase L in nanomolar concentrations. The replacement of the first residue (pXAAA), or both the first and the third residues (pXAXA), was also tolerated by the enzyme. In contrast, in all cases, the replacement of the second residue (pAXAA) resulted in the significant decrease of binding ability. Additionally, no more than two phosphonate modifications in the tetramer were allowed to retain the binding affinity to the enzyme. Although all three tetramers pAAXA were found to be potent enzyme binders, only tetramers modified by ribo- and xylo-2'-phosphonate unit X activated the RNase L-catalyzed cleavage of the RNA substrate. Surprisingly, tetramer pAAXA, modified by arabino-2'-phosphonate unit X, did not activate the enzyme and can be considered a potent antagonist. In comparison with their natural counterpart, the phosphonate analogues of the pA4 exhibit superior resistance toward nucleases present in the murine spleen homogenate.
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