Biologically Active Oligodeoxyribonucleotides - II<sup>1</sup>: Structure Activity Relationships of Anti-HIV-1 Pentadecadeoxyribonucleotides Bearing 5′-End-Modifications

Hotoda, Hitoshi; Momota, Kenji; Furukawa, Hidehiko; Nakamura, Takemichi; Kaneko, Masakatsu; Kimura, Satcshi; Shimada, Kawu

doi:10.1080/15257779408012159

Cited by 27 publications

(28 citation statements)

References 17 publications

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“…T1 contained three hydrophobic groups (one TBDPS and two DMTs) at each end of the helix. The IC 50 for T1 was 1.8 -0.7 mM, comparable to the previously reported IC 50 values of duplex and quadruplex inhibitors [3][4][5][6][7][8][9][10][11][12][13][14][15]. T2 had no hydrophobic group modifications and did not show the anti-HIV-1 fusion activity.…”

Section: Odns and Triplexessupporting

confidence: 66%

“…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].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Xu¹,

Zhang²,

Xu³

et al. 2015

Nucleic Acid Therapeutics

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Section: Odns and Triplexessupporting

confidence: 66%

Section: Introductionmentioning

confidence: 99%

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

Xu¹,

Zhang²,

Xu³

et al. 2015

Nucleic Acid Therapeutics

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“…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).…”

mentioning

confidence: 99%

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

Xu¹,

Cai²,

Chen

et al. 2013

Antimicrob Agents Chemother

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Discovery of new drugs for the treatment of AIDS typically possessing unique structures associated with novel mechanisms of action has been of great importance due to the quick drug-resistant mutations of HIV-1 strains. The work presented in this report describes a novel class of DNA duplex-based HIV-1 fusion inhibitors. Hydrophobic groups were introduced into a DNA duplex skeleton either at one end, at both ends, or in the middle. These modified DNA duplexes inhibited fusion between HIV-1 and human cell membranes at micro-or submicromolar concentrations. Respective inhibitors adopted an aptamer pattern instead of a base-pairing interaction pattern. Structure-activity relationship studies of the respective DNA duplexes showed that the rigid and negatively charged DNA skeletons, in addition to the presence of hydrophobic groups, were crucial to the anti-HIV-1 activity of these compounds. A fluorescent resonance energy transfer (FRET)-based inhibitory assay showed that these duplex inhibitors interacted with the primary pocket in the gp41 N-terminal heptad repeat (NHR) instead of interacting with the lipid bilayers.

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“…3, contained two guanosine clusters of four contiguous guanosine sequences like a G-quartet and the core sequence, the antiviral activity of ODN7 was diminished if the guanosine clusters were apart from the DmTr group at its 5' end. In addition, Hotoda et al (1994) also reported that an SA-1042 derivative bearing a long alkyl linker between the trityl-substituent and the 5' end of the SA-1042 sequence had greatly decreased activity. The minimum length of spacer between the G-quartet-like motif and the DmTr residue is probably two or three bases to maintain activity (Furukawa et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

“…Structures of DmTr-modified ODNs (DmTr-ODNs) were confirmed by negative ion LSI mass spectroscopy (VG70-4SE). Trityl-modified ODNs were prepared as described previously (Hotoda et al, 1994).…”

Section: Synthesis and Purification Of Oons And Omtrlinked Oonsmentioning

confidence: 99%

Antiviral and Biological Properties of Dimethoxytrityl-Linked Guanine-Rich Oligodeoxynucleotides that Inhibit Replication by Primary Clinical Human Immunodeficiency virus Type 1 Isolates

Momota

Furukawa

Kimura³

et al. 1997

Antivir Chem Chemother

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SummaryWe have investigated the biological and antiviral properties of a dimethoxytrityl (DmTr)-linked guanine (G)-rich oligodeoxynucleotide (ODN) with a phosphodiester linkage, 5A-1042 (5' DmTr-TGGGAGGTGGGTCTG 3'), that has been shown to exhibit potent inhibition of human immunodeficiency virus type 1 (HIV-l)-induced cytopathic effect. In a study of the modification of the sequences of SA-1042, it: was revealed that the inhibitory effect is exhibited in a highly sequencespecific manner, at the G-rich core sequence (5' TGGG 3'), especially near the 5' end. In a study of the gel mobility-antiviral activity relationship, DmTr modification and the G-rich core sequence of DmTr-ODNs were indispensable for the formation of a hyperstructure and for theirantiviral activity. HIV-induced syncytium formation in co-cultures of MOlT-4 cells and chronically infected MOlT-4/HIV-l m B cells was blocked by SA-1042 at a 50% inhibitory concentration (IC 50 ) of 6.5 r-tg ml'. Time-of-addition studies revealed that SA-1042 blocked virus attachment to cells. The susceptibility of 10 fresh HIV-l clinical isolates [nine with syncytium-inducing (51) phenotypes and one with a non-51 phenotype], and five laboratorystrains with both phenotypes to SA-1042 was assessed by a focus reduction assay using CD4+ Hela cells or by p24 antigen quantitative assay using human peripheral blood mononuclear cells. SA-1042 was active in both assays. These results suggest that SA-l042; which inhibits the adsorption and fusion steps of HIV·l replication through its hyperstructure formation and the G-rich core sequence, exhibits potent activity against primary clinical isolates.

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Biologically Active Oligodeoxyribonucleotides - II¹: Structure Activity Relationships of Anti-HIV-1 Pentadecadeoxyribonucleotides Bearing 5′-End-Modifications

Cited by 27 publications

References 17 publications

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

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

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

Antiviral and Biological Properties of Dimethoxytrityl-Linked Guanine-Rich Oligodeoxynucleotides that Inhibit Replication by Primary Clinical Human Immunodeficiency virus Type 1 Isolates

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Biologically Active Oligodeoxyribonucleotides - II1: Structure Activity Relationships of Anti-HIV-1 Pentadecadeoxyribonucleotides Bearing 5′-End-Modifications

Cited by 27 publications

References 17 publications

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

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

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

Antiviral and Biological Properties of Dimethoxytrityl-Linked Guanine-Rich Oligodeoxynucleotides that Inhibit Replication by Primary Clinical Human Immunodeficiency virus Type 1 Isolates

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Biologically Active Oligodeoxyribonucleotides - II¹: Structure Activity Relationships of Anti-HIV-1 Pentadecadeoxyribonucleotides Bearing 5′-End-Modifications