Biologically Active Oligodeoxyribonucleotides - IV: Anti-HIV-1 Activity of Tgggag Having Hydrophobic Substituent at Its 5′-End via Phosphodiester Linkage

Hotoda, Hitoshi; Koizumi, Makoto; Koga, Ryota; Momota, Kenji; Ohmine, Toshinori; Furukawa, Hidehiko; Nishigaki, Toshinori; Kinoshita, Takeshi; Kaneko, Masakatsu; Kimura, Satoshi; Shimada, Kaoru

doi:10.1080/07328319608002403

Cited by 15 publications

(19 citation statements)

References 9 publications

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“…The 6-mer sequence, also known as Hotoda’s sequence, forms a tetramolecular parallel G-quadruplex ( Figure 1 C). It has been shown that attachment of aromatic substituents at the 5′-end resulted in enhancement of anti-HIV-1 activity ( 15–17 ). Alterations in the structure [shortness of the sequence, substitution of dG to dT ( 15–17 ) or to 8-aza-3-deaza-2′-deoxyguanosine ( 18 )] which induce destabilization of the G-quadruplex structure have resulted in a drop in activity.…”

Section: Introductionmentioning

confidence: 99%

“…It has been shown that attachment of aromatic substituents at the 5′-end resulted in enhancement of anti-HIV-1 activity ( 15–17 ). Alterations in the structure [shortness of the sequence, substitution of dG to dT ( 15–17 ) or to 8-aza-3-deaza-2′-deoxyguanosine ( 18 )] which induce destabilization of the G-quadruplex structure have resulted in a drop in activity. The 17-mer sequence, T30177 (Zintevir, Figure 1 D) has been extensively studied due to observed high inhibition of HIV-1 integrase ( 19–21 ).…”

Section: Introductionmentioning

confidence: 99%

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Enhanced anti-HIV-1 activity of G-quadruplexes comprising locked nucleic acids and intercalating nucleic acids

Pedersen

Nielsen

et al. 2010

Nucleic Acids Research

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Two G-quadruplex forming sequences, 5′-TGGGAG and the 17-mer sequence T30177, which exhibit anti-HIV-1 activity on cell lines, were modified using either locked nucleic acids (LNA) or via insertions of (R)-1-O-(pyren-1-ylmethyl)glycerol (intercalating nucleic acid, INA) or (R)-1-O-[4-(1-pyrenylethynyl)phenylmethyl]glycerol (twisted intercalating nucleic acid, TINA). Incorporation of LNA or INA/TINA monomers provide as much as 8-fold improvement of anti-HIV-1 activity. We demonstrate for the first time a detailed analysis of the effect the incorporation of INA/TINA monomers in quadruplex forming oligonucleotides (QFOs) and the effect of LNA monomers in the context of biologically active QFOs. In addition, recent literature reports and our own studies on the gel retardation of the phosphodiester analogue of T30177 led to the conclusion that this sequence forms a parallel, dimeric G-quadruplex. Introduction of the 5′-phosphate inhibits dimerisation of this G-quadruplex as a result of negative charge–charge repulsion. Contrary to that, we found that attachment of the 5′-O-DMT-group produced a more active 17-mer sequence that showed signs of aggregation—forming multimeric G-quadruplex species in solution. Many of the antiviral QFOs in the present study formed more thermally stable G-quadruplexes and also high-order G-quadruplex structures which might be responsible for the increased antiviral activity observed.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Enhanced anti-HIV-1 activity of G-quadruplexes comprising locked nucleic acids and intercalating nucleic acids

Pedersen

Nielsen

et al. 2010

Nucleic Acids Research

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“…[30,34] Phenyl 2-cyanoethyl-N,N-diisopropylphosphoramidite was prepared according to the literature. [35] DNA/RNA synthesis reagents were purchased from Applied Biosystems.…”

Section: Methodsmentioning

confidence: 99%

Biologically Stable 2‐5A Analogues containing 3′‐O,4′‐C‐bridged Adenosine as Potent RNase L Agonists

et al. 2007

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“…In the same years, Hotoda and co-workers reported the synthesis of a mini-library based on the 5′-phosphodiester of d(TGGGAG) conjugated with different aromatic residues. From the anti-HIV screening of different modified 6-mer ODNs, no more active modified sequences were discovered [25]. Meanwhile, the same researchers reported the synthesis and anti-HIV-1 activity of a mini library of d(TGGGAG) with a 5′,3′-bis-conjugated lead sequence, wherein the 5′-end conjugation was carried out by an ether bond and the 3′-end by a phosphodiester bridge [26].…”

Section: The Discovery Of the First 5′-end Modified Of Hotoda’s Sementioning

confidence: 99%

Hotoda’s Sequence and Anti-HIV Activity: Where Are We Now?

2019

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The pharmacological relevance of ODNs forming G-quadruplexes as anti-HIV agents has been extensively reported in the literature over the last few years. Recent detailed studies have elucidated the peculiar arrangement adopted by many G-quadruplex-based aptamers and provided insight into their mechanism of action. In this review, we have reported the history of a strong anti-HIV agent: the 6-mer d(TGGGAG) sequence, commonly called “Hotoda’s sequence”. In particular, all findings reported on this sequence and its modified sequences have been discussed considering the following research phases: (i) discovery of the first 5′-modified active d(TGGGAG) sequences; (ii) synthesis of a variety of end-modified d(TGGGAG) sequences; (iii) biophysical and NMR investigations of natural and modified Hotoda’s sequences; (iv); kinetic studies on the most active 5′-modified d(TGGGAG) sequences; and (v) extensive anti-HIV screening of G-quadruplexes formed by d(TGGGAG) sequences. This review aims to clarify all results obtained over the years on Hotoda’s sequence, revealing its potentiality as a strong anti-HIV agent (EC50 = 14 nM).

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Biologically Active Oligodeoxyribonucleotides - IV: Anti-HIV-1 Activity of Tgggag Having Hydrophobic Substituent at Its 5′-End via Phosphodiester Linkage

Cited by 15 publications

References 9 publications

Enhanced anti-HIV-1 activity of G-quadruplexes comprising locked nucleic acids and intercalating nucleic acids

Enhanced anti-HIV-1 activity of G-quadruplexes comprising locked nucleic acids and intercalating nucleic acids

Biologically Stable 2‐5A Analogues containing 3′‐O,4′‐C‐bridged Adenosine as Potent RNase L Agonists

Hotoda’s Sequence and Anti-HIV Activity: Where Are We Now?

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