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
S. Lederman et al., 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, ANTISENSE & NUCLEIC ACID DRUG DEVELOPMENT, 6(4), 1996, pp. 281-289
Citations number
41
Categorie Soggetti
Medicine, Research & Experimental","Biothechnology & Applied Migrobiology
Phosphorothioate oligodeoxynucleotides belong to a class of polyanions
that bind to the third variable domain (v3) of HIV-1 gp120 and inhibi
t infectivity of a wide variety of HIV-1 isolates. This potent v3 bind
ing of phosphorothioate oligodeoxynucleotides, which is relatively ind
ependent of the nucleotide sequence of the oligodeoxynucleotides, decr
eases with chain length (below 18-mers) and is low for 8-mers, However
, recent studies have observed a nucleotide sequence-dependent augment
ation of phosphorothioate oligodeoxynucleotide binding to v3 for 8-mer
s that contain the S-dG(4) moth (e.g., SdT(2)G(4)T(2)) and have sugges
ted that formation of quadruple helical tetraplexes (G-tetrads) is ass
ociated with the acquisition of v3 binding ability by small phosphorot
hioate 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 phosphorothioa
te oligodeoxynucleotides (with similar lengths or related sequences) f
or (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 comp
ounds are used as competitors of the rgp120-binding of an alkylating p
hosphodiester 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-HI
V-1 infectivity for small (8-mer or 12-mer oligodeoxynucleotides) but
did not significantly augment the potency of 28-mers, Whereas tetraple
x 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 gel
s, suggesting that S-dG(4) moths may augment anti-HIV activity by mult
iple mechanisms.