Identification of a phosphodiester hexanucleotide that inhibits HIV-1 infection in vitro on covalent linkage of its 5'-end with a dimethoxytrityl residue.
It has been shown in previous reports that a guanine-rich phosphodiester oligonucleotide bearing a dimethoxytrityl (DmTr) residue on its 5'-terminal. DmTr-TGGGAGGTGGGTCTG (SA-1042), is an inhibitor of HIV-1 infection in vitro. SA-1042 interfered with the attachment of gp120 to the CD4 receptor and the subsequent entry stage of viral infection. We investigated the structure-activity relationship of the DmTr-conjugated oligomer by using 15-mer oligonucleotides with various nucleotide sequences. Results show that location of guanine nucleosides at the 5'-terminal and modification of the 5'-terminal with DmTr are essential for anti-HIV-1 activity. First, substitution of the guanine nucleoside close to the 5'-terminal of SA-1042 with another nucleotide prevented antiviral activity. Second, the existence of at least three consecutive guanine nucleosides adjacent to the 5'-terminal was required for the activity. Finally, modification of the 5'-terminal was essential for the activity. Based on these findings, the hexanucleotide, DmTr-TGGGAG, was identified as a potent inhibitor of HIV-1 infection. The hexamer was found to be capable of inhibiting the binding of gp120 to its receptor CD4 molecule, and it was also capable of inhibiting accessibility of anti-V3 monoclonal antibody to its ligand V3 peptide.
Furukawa
H
H
Biological Research Laboratories, Sankyo Co. Ltd, Tokyo, Japan.
Momota
K
K
Agatsuma
T
T
Yamamoto
I
I
Kimura
S
S
Shimada
K
K
D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism*; D000937:Antigen-Antibody Reactions / Q000187:drug effects; D001667:Binding, Competitive; D015704:CD4 Antigens / Q000378:metabolism*; D002461:Cell Line, Transformed; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects*; D015699:HIV Envelope Protein gp120 / Q000276:immunology / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D009838:Oligodeoxyribonucleotides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000821:virology; D014320:Triphenylmethyl Compounds / Q000737:chemistry / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects*
D019380:Anti-HIV Agents; D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; C059762:HIV envelope protein gp120 (305-321); D009838:Oligodeoxyribonucleotides; D010446:Peptide Fragments; C107785:SA 1080; D014320:Triphenylmethyl Compounds