Polydeoxyguanine motifs in a 12-mer phosphorothioate oligodeoxynucleotide augment binding to the v3 loop of HIV-1 gp120 and potency of HIV-1 inhibition independency of G-tetrad formation.
Phosphorothioate oligodeoxynucleotides belong to a class of polyanions that bind to the third variable domain (v3) of HIV-1 gp120 and inhibit infectivity of a wide variety of HIV-1 isolates. This potent v3 binding of phosphorothioate oligodeoxynucleotides, which is relatively independent of the nucleotide sequence of the oligodeoxynucleotides, decreases with chain length (below 18-mers) and is low for 8-mers. However, recent studies have observed a nucleotide sequence-dependent augmentation of phosphorothioate oligodeoxynucleotide binding to v3 for 8-mers that contain the S-dG4 motif (e.g., SdT2G4T2) and have suggested that formation of quadruple helical tetraplexes (G-tetrads) is associated with the acquisition of v3 binding ability by small phosphorothioate oligodeoxynucleotides. In the current study, a series of SdG4-containing oligodeoxynucleotides were synthesized with varying tandem length (including the 8-mer SdT2G4T2, the 12-mer SdG4T4G4, and the 28-mer SdG4(T4G4)3) and compared with phosphorothioate oligodeoxynucleotides (with similar lengths or related sequences) for (1) their inhibition of the binding of mAb 9284, which binds to the N-terminal portion of the v3 loop, (2) the values of Kc when these compounds are used as competitors of the rgp120-binding of an alkylating phosphodiester oligodeoxynucleotide probe, and (3) inhibition of HIV-1 infectivity in a cell-cell transmission model. The presence of S-dG4 motifs and the number of tandem motifs augmented v3 binding and anti-HIV-1 infectivity for small (8-mer or 12-mer oligodeoxynucleotides) but did not significantly augment the potency of 28-mers. Whereas tetraplex formation of SdT2G4T2 may contribute to its v3 binding, the 12-mer SdG4T4G4 does not migrate as the tetraplex on nonreducing gels, suggesting that S-dG4 motifs may augment anti-HIV activity by multiple mechanisms.
Lederman
S
S
Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Sullivan
G
G
Benimetskaya
L
L
Lowy
I
I
Land
K
K
Khaled
Z
Z
Cleary
A M
AM
Yakubov
L
L
Stein
C A
CA
D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology; D000911:Antibodies, Monoclonal; D004268:DNA-Binding Proteins / Q000737:chemistry; D015699:HIV Envelope Protein gp120 / Q000737:chemistry*; D015497:HIV-1 / Q000472:pathogenicity*; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides / Q000737:chemistry* / Q000494:pharmacology; D011068:Poly G / Q000737:chemistry*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012996:Solutions; D013873:Thionucleotides / Q000737:chemistry* / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D000911:Antibodies, Monoclonal; D004268:DNA-Binding Proteins; D015699:HIV Envelope Protein gp120; D009838:Oligodeoxyribonucleotides; D012996:Solutions; D013873:Thionucleotides; D011068:Poly G