Inhibition of human immunodeficiency virus type 1 replication by P-stereodefined oligo(nucleoside phosphorothioate)s in a long-term infection model.
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 microM 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 microM) 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.
Inagawa
Takubumi
T
Department of Industrial Chemistry, Chiba Institute of Technology, 2-17-1 Tsudanuma, Narashino, Japan.
Nakashima
Hideki
H
Karwowski
Boleslaw
B
Guga
Piotr
P
Stec
Wojciech J
WJ
Takeuchi
Hiroaki
H
Takaku
Hiroshi
H
D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology; D001483:Base Sequence; D002460:Cell Line; D015750:Genes, gag; D015757:Genes, rev; D015756:Genes, tat; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008954:Models, Biological; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D020319:Oligodeoxyribonucleotides, Antisense / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D013237:Stereoisomerism; D013873:Thionucleotides / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects*
D019380:Anti-HIV Agents; D009838:Oligodeoxyribonucleotides; D020319:Oligodeoxyribonucleotides, Antisense; D013873:Thionucleotides