Short, Terminally Phosphorylated Oligoriboguanylic Acids Effectively Inhibit Cytopathicity Caused by Human Immunodeficiency Virus

Fujihashi, Toshiaki; Sakata, Toshiya; Kaji, Akira; Kaji, Hideko

doi:10.1006/bbrc.1994.2316

Cited by 10 publications

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“…In our continued attempts to develop an effective anti-HIV agent (19,20,26,52), we found that 4,9-halogenated gomisin J derivatives have potent anti-HIV activities with high selective indices (some of them are over 300). We conclude that these derivatives exert their anti-HIV activities through their inhibitory effects on HIV-1 RT.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Anti-human immunodeficiency virus (HIV) activities of halogenated gomisin J derivatives, new nonnucleoside inhibitors of HIV type 1 reverse transcriptase

Fujihashi

Hara

Sakata

et al. 1995

Antimicrob Agents Chemother

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Lignans are phenylpropanoid dimers distributed very widely in the plant kingdom. There are various kinds of lignan depending on the mode of dimerization of phenylpropanoid. Gomisin is a dibenzocyclooctadiene-type lignan compound and a component of Schizandra fruit extracts (30-32, 70). There are various types of gomisins, A, B, C, D, E, F, G, J, and N; some possess central nervous system depressant, analgesic, antitussive, and/or Ca antagonist activities (42, 69). As for the antiviral activities of lignans, it has been reported that tetrahydronaphthalene-type lignans have selective inhibitory activities on herpes simplex virus and cytomegalovirus (41, 43) and that dibenzylbutanolide-type lignans have an inhibitory effect on human immunodeficiency virus (HIV) replication (63). However, the ratio of toxic dose to effective dose (selective index) of dibenzylbutanolide-type lignan was no more than 5, suggesting that this could not be used as a clinically effective anti-HIV agent.In continuation of our search for anti-HIV agents (19, 20, 26, 52), we report in this paper new gomisin J derivatives which have potent anti-HIV activities with much higher selective indices than that of dibenzylbutanolide-type lignan. The highest selective index among gomisin J derivatives was over 300. MATERIALS AND METHODSChemicals. Gomisin J was isolated as previously described (32). Halogenated derivatives (Fig. 1) of gomisin J were synthesized from gomisin J by using halogenizing agents such as N-bromosuccinimide. Detailed descriptions of synthesis and characterization will be published elsewhere. Structures of pure, newly synthesized compounds were determined by nuclear magnetic resonance and infrared analyses. These compounds were kindly provided by Tanaka, Tsumura Central Research Institute, Ibaraki, Japan. 3Ј-Azido-3Ј-deoxythymidine (AZT) and 2Ј,3Ј-ddC were purchased from Sigma Chemical Co. ). These cells were grown in 25 mM HEPES (N-hydroxyethylpiperazine-NЈ-2-ethanesulfonic acid)-buffered RPMI 1640 (GIBCO) supplemented with 10% fetal calf serum, 100 U of penicillin per ml, 100 g of streptomycin per ml, and 0.25 g of amphotericin B per ml. At this concentration, amphotericin B is effective as an antimycotic in tissue culture but has no inhibitory activity for HIV replication (50, 64).

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Section: Discussionmentioning

confidence: 99%

“…In continuation of our search for anti-HIV agents (19,20,26,52), we report in this paper new gomisin J derivatives which have potent anti-HIV activities with much higher selective indices than that of dibenzylbutanolide-type lignan. The highest selective index among gomisin J derivatives was over 300.…”

mentioning

confidence: 99%

Anti-human immunodeficiency virus (HIV) activities of halogenated gomisin J derivatives, new nonnucleoside inhibitors of HIV type 1 reverse transcriptase

Fujihashi

Hara

Sakata

et al. 1995

Antimicrob Agents Chemother

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“…The degree of interaction was dependent on the length of the oligonucleotide studied, with a rapid decrease in binding affinity observed for compounds shorter than 18 nucleotides. However, the short G-rich oligonucleotides also interact with the V3 loop of HIV-1 and have anti-HIV-1 activity (1,5,7,14,18,22,27,38,46). To compare the characteristics of the oligonucleotides, including the dG3T4G3-s, dG10-s, and dT10-s interactions with the V3 loop or the CD4-binding sites on HIV-1 gp120, another series of experiments studied the oligonucleotide-mediated inhibition of the binding of an FITCcoupled anti-V3 HIV-1 gp120 MAb to the V3 loop of HIV-1 gp 120 or of an FITC-coupled anti-CD4 MAb to the CD4 binding site on HIV-1 gp120.…”

Section: Mechanism Of Hiv-1 Infection Inhibitionmentioning

confidence: 99%

“…Stein et al have also proposed that SdC28 specifically interacts with the positively charged V3 loop of HIV-1 gp120 (37). More recently, a few workers have described the interactions of short, G-rich oligonucleotides, which also interfere with the gp120-CD4 interaction or HIV integrase activity, and were found to have anti-HIV-1 activity (1,5,7,14,18,22,27,38,46). Physical characterizations of these oligonucleotides have demonstrated that they form tetramers stabilized by G quartets (16,17,19,28,39).…”

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confidence: 99%

Inhibition of Human Immunodeficiency Virus Type 1 Activity In Vitro by a New Self-Stabilized Oligonucleotide with Guanosine-Thymidine Quadruplex Motifs

Suzuki¹,

Miyano-Kurosaki

Kuwasaki³

et al. 2002

J Virol

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An oligonucleotide with a dimeric hairpin guanosine quadruplex (basket type structure) (dG3T4G3-s), containing phosphorothioate groups, was able to inhibit human immunodeficiency virus type 1 (HIV-1)-induced syncytium formation and virus production (as measured by p24 core antigen expression) in peripheral blood mononuclear cells. This oligonucleotide lacks primary sequence homology with the complementary (antisense) sequences to the HIV-1 genome. Furthermore, this oligonucleotide may have increased nuclease resistance. The activity of this oligonucleotide was increased when the phosphodiester backbone was replaced with a phosphorothioate backbone. In vivo results showed that dG3T4G3-s was capable of blocking the interaction between gp120 and CD4. We also found that dG3T4G3-s specifically inhibits the entry of T-cell line-tropic HIV-1 into cells. This compound is a viable candidate for evaluation as a therapeutic agent against HIV-1 in humans.

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“…In continuing our effort to obtain effective anti-HIV agents, [29][30][31][32][33] we describe in this article potent new nonnucleoside HIV-1 RT inhibitors: synthetic THN lignan derivatives.…”

Section: Introductionmentioning

confidence: 99%

Tetrahydronaphthalene Lignan Compounds as Potent Anti-HIV Type 1 Agents

Hara¹,

Fujihashi²,

Sakata³

et al. 1997

AIDS Research and Human Retroviruses

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Anti-HIV-1 activity of tetrahydronaphthalene (THN) derivatives of lignan compounds was studied. THN derivatives prevented cell death caused by HIV-1 infection in MT-4 cells. They also inhibited giant cell formation by HIV-1 in Sup-T1 cells, and p24 production in HIV-1-infected H9 cells. The 50% effective concentration (ED50) of the most active compound, 1737 [5,6,7-trimethoxy-4-(3,4,5-trimethoxyphenyl)-1,3,3a,4,9,9a-hexahydron aphtho[2,3-c]thiophene], for inhibition of the cytopathic effects of HIV-1 infection ranged from 0.15 to 0.8 microM. The 50% cytotoxic concentration (CC50) of compound 1737 measured by the viability of MT-4 cells was 58 microM, indicating a selective index (CC50/ED50) of 70-400. Substitution of the phenyl ring with other structures markedly decreased cytotoxicity but did not affect the antiviral activity of the compounds. This resulted in compounds with a high selective index. One such compound was 1738 [7-methoxy5,6-methylenedioxy-4-(4-benzyloxy-3-methoxyphenyl)1,3,3a ,4,9,9a-hexahydronaphtho[2,3-c]thiophene], with a selective index higher than 770. The time-of-addition experiment indicated that these compounds acted at or near the reverse transcription step of the HIV-1 life cycle. THN derivatives inhibited HIV-1 reverse transcriptase (RT) in vitro at a concentration of 1 microM. Resistant viruses selected in the presence of THN derivatives showed some degree of cross-resistance to other nonnucleoside RT inhibitors, but not to the nucleoside RT inhibitor, AZT. THN derivatives failed to inhibit replication of pyridinone- and nevirapine-resistant HIV strains. However, compound 1737 inhibited replication of a TIBO-resistant strain more effectively than the wild-type HIV-1. Consistent with this result, compound 1737 also inhibited TIBO-resistant RT more effectively than the wild-type RT in vitro. These results suggested that THN derivatives interact with RT in a manner similar to but slightly different from that of other nonnucleoside HIV-1 RT inhibitors.

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Short, Terminally Phosphorylated Oligoriboguanylic Acids Effectively Inhibit Cytopathicity Caused by Human Immunodeficiency Virus

Cited by 10 publications

References 0 publications

Anti-human immunodeficiency virus (HIV) activities of halogenated gomisin J derivatives, new nonnucleoside inhibitors of HIV type 1 reverse transcriptase

Anti-human immunodeficiency virus (HIV) activities of halogenated gomisin J derivatives, new nonnucleoside inhibitors of HIV type 1 reverse transcriptase

Inhibition of Human Immunodeficiency Virus Type 1 Activity In Vitro by a New Self-Stabilized Oligonucleotide with Guanosine-Thymidine Quadruplex Motifs

Tetrahydronaphthalene Lignan Compounds as Potent Anti-HIV Type 1 Agents

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