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Chiral and achiral phosphorothioate analogs of 2-5A: stereochemical course of RNase L

Conference · · Fed. Proc., Fed. Am. Soc. Exp. Biol.; (United States)
OSTI ID:5022048
; ;
The trimer and tetramer phosphorothioate (thio) analogs of 2-5A have been enzymatically synthesized from (Sp)ATP..cap alpha..S, (Sp)ATP..beta..S, (Rp)ATP..beta..S and ATP..gamma..S by 2-5A synthetase from IFN-..beta..-treated L929 cell extracts and lysed rabbit reticulocytes. The structures of these compounds have been determined by HPLC, enzymatic digestions and TLC. The biological activity of these thio analogs of 2-5A was determined by binding and activation of RNase L. The thio analog from (Sp)ATP..cap alpha..S, with the Rp configuration in the 2-5-phosphorothiodiester linkages and the Sp configuration at the ..cap alpha..phosphate of the 5'-terminus, exhibits substantially increased biological effects compared to 2-5A; this thio analog displaces 2-5-p/sub 3/A/sub 4/(/sup 32/P)pCp from RNase L better than does naturally occurring 2-5A. Also, it activates RNase L to hydrolyze either polyU-3'-(/sup 32/P)Cp (core cellulose assay) or 28S and 18S RNAs (rRNA cleavage assay) at one log lower concentration (10/sup -10/ M) than does authentic 2-5A (10/sup -9/M). The thio-substituted analogs of 2-5A with either Sp- or Rp-chirality at the ..beta..-phosphate as well as achiral thio-substitution on the ..gamma..-phosphate were biologically active at concentrations as low as 10/sup -9/, 10/sup -8/, and 10/sup -9/ M, respectively, in rRNA cleavage assays using L929 and LMTK/sup -/ cell extracts.
Research Organization:
Temple Univ. School of Medicine, Philadelphia, PA
OSTI ID:
5022048
Report Number(s):
CONF-8606151-
Conference Information:
Journal Name: Fed. Proc., Fed. Am. Soc. Exp. Biol.; (United States) Journal Volume: 45:6
Country of Publication:
United States
Language:
English

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Related Subjects

550201* -- Biochemistry-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
ADENOSINE
ATP
BETA DECAY RADIOISOTOPES
BETA-MINUS DECAY RADIOISOTOPES
BIOCHEMICAL REACTION KINETICS
BIOLOGICAL MATERIALS
BLOOD
BLOOD CELLS
BODY FLUIDS
CHROMATOGRAPHY
DAYS LIVING RADIOISOTOPES
ENZYME ACTIVITY
ENZYMES
ERYTHROCYTES
ESTERASES
HYDROLASES
ISOTOPE APPLICATIONS
ISOTOPES
KINETICS
LIGHT NUCLEI
LIQUID COLUMN CHROMATOGRAPHY
MATERIALS
MOLECULAR STRUCTURE
NUCLEI
NUCLEIC ACIDS
NUCLEOSIDES
NUCLEOTIDES
ODD-ODD NUCLEI
ORGANIC COMPOUNDS
OXYGEN COMPOUNDS
PHOSPHATES
PHOSPHODIESTERASES
PHOSPHORUS 32
PHOSPHORUS COMPOUNDS
PHOSPHORUS ISOTOPES
RADIOISOTOPES
REACTION KINETICS
RETICULOCYTES
RIBOSIDES
RNA
RNA-ASE
SEPARATION PROCESSES
STEREOCHEMISTRY
TRACER TECHNIQUES