Identification of a phosphodiester hexanucleotide that inhibits HIV-1 infection in vitro on covalent linkage of its 5'-end with a dimethoxytrityl residue.

Abstract

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.

• Authors: H Furukawa, K Momota, T Agatsuma, I Yamamoto, S Kimura, K Shimada
• Journal: Antisense & nucleic acid drug development (Antisense Nucleic Acid Drug Dev) Vol. 7 Issue 3 Pg. 167-75 (Jun 1997) ISSN: 1087-2906 [Print] United States
• PMID: 9212907 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Anti-HIV Agents
• Antibodies, Monoclonal
• CD4 Antigens
• HIV Envelope Protein gp120
• HIV envelope protein gp120 (305-321)
• Oligodeoxyribonucleotides
• Peptide Fragments
• SA 1080
• Trityl Compounds

Topics

• Anti-HIV Agents (chemistry, pharmacology)
• Antibodies, Monoclonal (immunology, metabolism)
• Antigen-Antibody Reactions (drug effects)
• Binding, Competitive
• CD4 Antigens (metabolism)
• Cell Line, Transformed
• Cytopathogenic Effect, Viral (drug effects)
• HIV Envelope Protein gp120 (immunology, metabolism)
• HIV-1 (drug effects, physiology)
• Humans
• Oligodeoxyribonucleotides (chemical synthesis, chemistry, metabolism, pharmacology)
• Peptide Fragments (immunology, metabolism)
• Protein Binding (drug effects)
• Structure-Activity Relationship
• T-Lymphocytes (virology)
• Trityl Compounds (chemistry, pharmacology)
• Virus Replication (drug effects)