Inhibition of human immunodeficiency virus type 1 replication by P‐stereodefined oligo(nucleoside phosphorothioate)s in a long‐term infection model

FEBS Letters

Takeuchi, Hiroaki¹  Guga, Piotr²  Takaku, Hiroshi¹  Nakashima, Hideki³  Inagawa, Takubumi¹  Karwowski, Boleslaw²  Stec, Wojciech J.² 

[1] Department of Industrial Chemistry, Chiba Institute of Technology, 2-17-1 Tsudanuma, Narashino, Chiba 275-0016, Japan;Centre of Molecular and Macromolecular Studies, Polish Academy of Science, Department of Bioorganic Chemistry, Lodz, Poland;St. Marianna University, School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, Japan

关键词: Antisense therapy;    Oligo(nucleoside phosphorothioate)s (S-ODNs);    Diastereomerically pure S-ODN;    Nuclease resistance;    Anti-HIV-1 activity;    Long-term assay;    gag;    rev and tat genes;   

DOI  :  10.1016/S0014-5793(02)03235-0

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

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.

【 授权许可】

Unknown