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Inhibition of human immunodeficiency virus type 1 replication by P‐stereodefined oligo(nucleoside phosphorothioate)s in a long‐term infection model
Author(s) -
Inagawa Takubumi,
Nakashima Hideki,
Karwowski Boleslaw,
Guga Piotr,
Stec Wojciech J.,
Takeuchi Hiroaki,
Takaku Hiroshi
Publication year - 2002
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(02)03235-0
Subject(s) - diastereomer , oligonucleotide , reverse transcriptase , nucleoside , microbiology and biotechnology , antigen , antisense therapy , biology , group specific antigen , messenger rna , clone (java method) , nucleoside analogue , sense (electronics) , rna , virology , chemistry , human immunodeficiency virus (hiv) , stereochemistry , dna , biochemistry , gene , immunology , locked nucleic acid
Oligo(nucleoside phosphorothioate)s (S‐ODNs), if prepared by conventional methods, consist of a mixture of diastereomers by virtue of the asymmetry of the phosphorus atom involved in the internucleotide linkages. This may affect the stability of the complexes formed between S‐ODNs and complementary oligoribonucleotides, which is commonly accepted as the most important factor in determining the efficacy of an antisense approach. Using HIV‐1‐infected MOLT‐4 cells via a long‐term culture approach, we studied the influence of the P‐chirality sense of stereodefined 28mer oligo(nucleoside phosphorothioate)s, [All‐Rp]‐S‐ODN‐ gag ‐28‐AUG and [All‐Sp]‐S‐ODN‐ gag ‐28‐AUG, complementary to the sequence starting at the AUG initiation codon of the gag mRNA of HIV‐1, upon the anti‐HIV‐1 activity. The [All‐Sp]‐S‐ODN‐ gag ‐28‐AUG at a low concentration of 0.5 μM can completely suppress HIV‐1 gag p24 antigen expression in HIV‐1‐infected MOLT‐4 clone 8 cells for 32 days. Cells treated with [All‐Rp]‐S‐ODN‐ gag ‐28‐AUG (0.5 μM) showed a high level of the antigen expression at day 16. Furthermore, satisfactory suppression could not be achieved from a random [Mix]‐S‐ODN‐ gag ‐28‐AUG, consisting of a diastereomeric mixture of the oligonucleotides. Our results suggest that chemotherapy based upon the use of stereodefined antisense [All‐Sp] S‐ODN may be a more effective method for reducing the viral burden in HIV‐1‐infected individuals.