Synthesis, Characterization, and Biological Properties of 8-Azido- and 8-Amino-Substituted 2‘,5‘-Oligoadenylates

Abstract

A series of 8-azido- and 8-amino-substituted 2',5'-oligoadenylatyes was prepared by a uranyl-ion catalyzed polymerization of the corresponding 8-substituted adenosine phosphorimidazolide. Subsequent 5'-dephosphorylation of the resulting 5'-phosphoryl 2',5'-linked oligomers with alkaline phosphatase gave the corresponding core oligomers. The CD spectra indicated that the 8-aminoadenosine analogue of the 2',5'-linked trimer has an anti-orientation as in naturally occurring 2',5'-oligoadenylates, while 8-azido-substituted 2',5'-oligoadenylates have a syn-orientation. The 8-substituted oligomers showed enhanced resistance against digestion by snake venom phosphodiesterase. The 2',5'-linked 8-azidoadenylate trimer and tetramer displayed strong RNase L binding and activating ability, although the corresponding dimer is devoid of such activities. In contrast, very low or no RNase L binding and activating ability were observed in the 8-aminoadenosine analogue of 2',5'-oligoadenylates. Results indicate that the bulkiness and ionic character of the 8-substituting group have significant effects on the ability of these analogues to bind and activate RNase L. Furthermore, the orientation of the glycosidic base in the 2-5A analogues may change from syn to anti during binding to RNase L. The 8-azidoadenosine analogues of 2-5A will be useful tools in the photoaffinity labeling of RNase L, due to their strong RNase L binding ability. In addition, these 8-azidoadenosine compounds may be considered as candidates for experimental therapeutic agents because they have enhanced stability to enzyme degradation while retaining the ability to activate RNase L.

RNA-Seq based transcriptome analysis during bovine viral diarrhoea virus (BVDV) infection

“…OAS1Y , Mx1 , and ISG15 , which have direct antiviral activity, were found to be downregulated during BVDV infection. 2′-5’oligoadenylate synthase (OAS), a member of the double-stranded RNA family, is an important antiviral protein induced by IFN and is involved in cellular innate immune defence [64]. OAS protein can be activated by replication intermediate dsRNA, and activated OAS can catalyse the synthesis of 2′-5′ oligoadenylate (2′-5’A) [65].…”

Combinatorial Multinuclear NMR and X-ray Diffraction Studies of Uranium(VI)-Nucleotide Complexes

“…The interaction between uranium(VI) and nucleotides and nucleic acids has been intensively studied; two aspects are of particular importance. A number of studies focused on the application of uranium(VI) as catalyst in the synthesis of 2‘−5‘-linked oligonucleotides with high regio- and stereoselectivity. − Another intensively studied field is the application of the uranyl ion as photochemical agent for cleavage of nucleic acids. − The uranyl ion, UO 2 2+ , has two oxygen ligands, so-called “yl”-oxygens, that are chemically inert under most circumstances, while the exchangeable ligands are all located in a plane perpendicular to the linear UO 2 unit. Hence, the steric requirements in ligand substitution reactions and in template and catalytic reactions are strict, one of the prerequisites for selectivity in these types of reactions.…”

Synthesis of (2'-5')-triadenylate and their analogues using O-nucleophilic catalysis of internucleotide coupling reaction

“…2-5A an a logues with chem i cal mod i fi ca tions, in clud ing those that in crease the nuclease re sis tance, of ten re veal higher bi o log i cal activ ity. A broad va ri ety of 2-5A an a logues with mod ified car bo hy drate res i dues, internucleotide phos phates, and heterocyclic bases has been ob tained [1,2,[6][7][8][9][10][11][12]. Thus, triadenylate 1b mod i fied with epoxyadenosine is known to be the in hib i tor of post-trans plan ta tion tis sue re jec tion [12] and was shown to pos sess cardioprotecting fea tures [13].…”