Polydeoxyguanine motifs in a 12-mer phosphorothioate oligodeoxynucleotide augment binding to the v3 loop of HIV-1 gp120 and potency of HIV-1 inhibition independently 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-dG(4) moth (e.g., SdT(2)G(4)T(2)) 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 SdG(4)-containing oligodeoxynucleotides were synthesized with varying tandem length (including the 8-mer SdT(2)G(4)T(2), the 12-mer SdG(4)T(4)G(4), and the 28-mer SdG(4)(T(4)G(4))(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 K-c 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-dG(4) moths and the number of tandem moths 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 SdT(2)G(4)T(2) may contribute to its v3 binding, the 12-mer SdG(4)T(4)G(4) does not migrate as a tetraplex on nonreducing gels, suggesting that S-dG(4) moths may augment anti-HIV activity by multiple mechanisms.