Biologically active oligodeoxyribonucleotides—IX.1 Synthesis and anti-HIV-1 activity of hexadeoxyribonucleotides, TGGGAG, bearing 3′- and 5′-end-modification

DNA Duplexes with Hydrophobic Modifications Inhibit Fusion between HIV-1 and Cell Membranes

“…Structural-activity relationship analysis showed that the presence of a DNA duplex and hydrophobic groups was crucial for the anti-HIV-1 activity observed, although the locations of the hydrophobic groups in the duplex and the sequence composition seemed not to be critical to the activity of the respective DNA duplexes tested. The modified DNA duplexes showed anti-HIV-1 activity at low M concentrations comparable to those of a previously described G-quadruplex HIV-1 entry inhibitor (17)(18)(19)(20)(21)(22)(23)(24). These duplex inhibitors were found to be interacting with the HIV-1 gp41 NHR deep pocket to prevent 6HB formation between the gp41 NHR and CHR.…”

“…In contrast to Hotoda's quadruplex inhibitors d(TGGGAG) 4 (17)(18)(19)(20)(21)(22)(23)(24), the duplex inhibitors reported in this paper can be extensively modified based on the location of the hydrophobic groups and skeleton length, thereby presenting more opportunities for modification.…”

“…These aptamers fold into defined three-dimensional (3D) structures and interact with HIV-1-associated proteins, such as HIV-1 reverse transcriptases (6,7), RNase H (8), Tat proteins (9), integrase (10)(11)(12)(13), and surface glycoproteins (14,15). A subcategory of aptamers possess an additional intermolecular assembly feature such as the quadruplex d(TGGGAG) 4 described by Hotoda et al, which was assembled by four 6-mer G-rich sequences in parallel with the 5=-end attaching to aromatic substituents of adequate size, such as tert-butyldiphenylsilyl (TBDPS) and 4=4-dimethoxytriphenyl (DMT) (16)(17)(18)(19)(20)(21)(22)(23)(24). These quadruplexes are aptamer-like since they interact with the V3 loop or the CD4 binding site on viral gp120, preventing viral adhesion and fusion with target cells (17,25,26).…”

“…A subcategory of aptamers possess an additional intermolecular assembly feature such as the quadruplex d(TGGGAG) 4 described by Hotoda et al, which was assembled by four 6-mer G-rich sequences in parallel with the 5=-end attaching to aromatic substituents of adequate size, such as tert-butyldiphenylsilyl (TBDPS) and 4=4-dimethoxytriphenyl (DMT) (16)(17)(18)(19)(20)(21)(22)(23)(24). These quadruplexes are aptamer-like since they interact with the V3 loop or the CD4 binding site on viral gp120, preventing viral adhesion and fusion with target cells (17,25,26). Although there was no sequential specificity for the targeting interaction, the whole complex still needs to assemble into a rigid, defined framework possessing negative charges and hydrophobic groups.…”

DNA Triplex-Based Complexes Display Anti-HIV-1-Cell Fusion Activity

“…Nearly 20 years ago, researchers discovered a category of DNA G-quadruplexbased inhibitors that display an anti-HIV-1 fusion activity [2]. Among these inhibitors, the most representative structure is Hotoda's sequence, d(TGGGAG), which interacts with the V3 loop or CD4-binding site of viral glycoprotein 120 (gp120) [3][4][5][6][7][8][9][10][11][12][13]. Recently, we designed a novel class of DNA duplex-based HIV-1 fusion inhibitors, which have hydrophobic groups at several selected positions [14,15].…”