Therapeutic agents with dramatic antiretroviral activity and little toxicity at effective doses: aromatic polycyclic diones hypericin and pseudohypericin.

Meruelo, Daniel; Lavie, Gad; Lavie, David

doi:10.1073/pnas.85.14.5230

Cited by 401 publications

(263 citation statements)

References 26 publications

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“…Hypocrellin has been used as a phototherapeutic agent for various skin diseases and tumors and has been taken orally as a folk medicine for several centuries in China (Diwu & Lown, 1990;Diwu et al, 1989). Like the related polycyclic quinone hypericin (Meruelo et al, 1988Degar et al, 1992;Lenard et al, 1993;Carpenter & Kraus, 1991), hypocrellin A possesses light-induced toxicity against the human immunodeficiency virus, HIV, and related viruses (Hudson et al, 1994). This common property of hypocrellin A and hypericin has led us to examine in more detail the similarities and differences between these chromophores.…”

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confidence: 99%

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Roles of Oxygen and Photoinduced Acidification in the Light-Dependent Antiviral Activity of Hypocrellin A

Fehr¹,

Carpenter²,

Wannemuehler³

et al. 1995

Biochemistry

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Hypocrellin A displays photoinduced antiviral activity, in particular against the human immunodeficiency virus (HIV), as does its counterpart, hypericin. Although hypocrellin A, like hypericin, executes an excitedstate intramolecular proton transfer, it differs from hypericin in two important ways. Unlike hypericin, hypocrellin A absolutely requires oxygen for its antiviral activity. Also, whereas we have previously demonstrated that hypericin functions as a light-induced proton source, we do not observe that hypocrellin A acidifies its surrounding medium in the presence of light. These results are discussed in the context of the ground-and excited-state photophysics of hypericin and its mechanisms of photoinduced virucidal activity. ABSTRACT: Hypocrellin A displays photoinduced antiviral activity, in particular against the human immunodeficiency virus (HIV), as does its counterpart, hypericin. Although hypocrellin A, like hypericin, executes an excited-state intramolecular proton transfer, it differs from hypericin in two important ways. Unlike hypericin, hypocrellin A absolutely requires oxygen for its antiviral activity. Also, whereas we have previously demonstrated that hypericin functions as a light-induced proton source, we do not observe that hypocrellin A acidifies its surrounding medium in the presence of light. These results are discussed in the context of the ground-and excited-state photophysics of hypericin and its mechanisms of photoinduced virucidal activity.

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confidence: 99%

“…Hypericin has a large triplet yield r0.70 in ethanol (Jardon et al, 1986)] and is capable of generating significant quantities of singlet oxygen (Meruelo et al, 1988Degar et al, 1992;Lenard et al, 1993). The virucidal activity of hypericin results, in part, from production of singlet oxygen.…”

mentioning

confidence: 99%

Roles of Oxygen and Photoinduced Acidification in the Light-Dependent Antiviral Activity of Hypocrellin A

Fehr¹,

Carpenter²,

Wannemuehler³

et al. 1995

Biochemistry

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“…A majority of the herb's antidepressant activity have recently been attributed to hyperforin and adhyperforin, and these compounds also possess antibacterial and cell growth inhibitory activity (1)(2)(3)14). The naphthodianthrone compounds, hypericin and its major metabolite pseudohypericin, have been shown to possess potent antiviral and cytotoxic properties upon light exposure (10)(11)(12)15).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the Light-Sensitive Cytotoxicity of Hypericum perforatum Extracts, Fractions, and Pure Compounds

Schmitt

Liu

Murphy

et al. 2006

J. Agric. Food Chem.

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Hypericum perforatum (Hp) is known for possessing antidepressant and antiviral activities. Despite its use as an alternative to conventional antidepressants, the identification of the cytotoxic chemicals derived from this herb is incomplete. In this study, the cytotoxicity of Hp extracts prepared in solvents ranging in polarity, fractions of one extract, and purified compounds were examined in three cell lines. All extracts exhibited significant cytotoxicity; those prepared in ethanol (no hyperforin, 3.6 μM hypericin, and 134.6 μM flavonoids) showed between 7.7 and 77.4% cell survival (p < 0.0001 and 0.01), whereas the chloroform and hexane extracts (hyperforin, hypericin, and flavonoids not detected) showed approximately 9.0 (p < 0.0001) and 4.0% (p < 0.0001) survival. Light-sensitive toxicity was observed primarily with the ethanol extracts sequentially extracted following removal of material extracted in either chloroform or hexane. The absence of light-sensitive toxicity with the Hp extracts suggests that the hypericins were not playing a prominent role in the toxicity of the extracts.

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“…variety of natural products have been described as anti-HIV agents (22), such as ingenol derivatives (23), betulinic acid and its derivatives (24,25), and hypericin (26,27). On the contrary, few natural inhibitors against plant-infecting viruses were reported except the anti-TMV agent pyrroloisoquinoline alkaloids (28).…”

Section: Discussionmentioning

confidence: 99%

Seco -pregnane steroids target the subgenomic RNA of alphavirus-like RNA viruses

Wang²,

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Plants have evolved multiple mechanisms to selectively suppress pathogens by production of secondary metabolites with antimicrobial activities. Therefore, direct selections for antiviral compounds from plants can be used to identify new agents with potent antiviral activity but not toxic to hosts. Here, we provide evidence that a class of compounds, seco-pregnane steroid glaucogenin C and its monosugar-glycoside cynatratoside A of Strobilanthes cusia and three new pantasugar-glycosides of glaucogenin C of Cynanchum paniculatum, are effective and selective inhibitors to alphavirus-like positive-strand RNA viruses including plant-infecting tobacco mosaic virus (TMV) and animal-infecting Sindbis virus (SINV), eastern equine encephalitis virus, and Getah virus, but not to other RNA or DNA viruses, yet they were not toxic to host cells. In vivo administration of the compounds protected BALB/c mice from lethal SINV infection without adverse effects on the mice. Using TMV and SINV as models, studies on the action mechanism revealed that the compounds predominantly suppress the expression of viral subgenomic RNA(s) without affecting the accumulation of viral genomic RNA. Our work suggested that the viral subgenomic RNA could be a new target for the discovery of antiviral drugs, and that seco-pregnane steroid and its four glycosides found in the two medicinal herbs have the potential for further development as antiviral agents against alphavirus-like positive-strand RNA viruses.antiviral drugs ͉ Strobilanthes cusia ͉ Cynanchum atratum V iruses replicate in host cells by hijacking the host-cell metabolic machinery. It is therefore difficult for antiviral therapies to inhibit only viral functions but spare host cellular processes. Nevertheless, great progress has been achieved over the past decades in antiviral research and therapy to reduce morbidity and mortality in virus-infected individuals (1, 2), and many antiviral drugs have been approved in recent years, most of which targeted either viral proteins or host cellular proteins. However, some of these compounds might induce the resistance of viruses to them and cause cell toxicity (3-5). The continuing emergence of highly pathogenic viruses like avian influenza viruses and severe acute respiratory syndrome coronavirus underscores the importance of advancing the search for effective antiviral agents. Plants have evolved constitutive and inducible defense mechanisms by producing a vast array of secondary metabolites against various microbial pathogens (6). Many herbaceous plants have been used in traditional Chinese medicine to treat viral diseases (7). It is conceivable that antiviral compounds would occur in plants as part of their innate defense arsenal, and the vast assortment of secondary metabolites could serve as a large pool for screening for previously undescribed antiviral compounds with a selective target spectrum and nontoxic to the host plants. Here, we provide evidence that a class of compounds, the seco-pregnane steroid and its glycosides from Strobilanthe...

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Therapeutic agents with dramatic antiretroviral activity and little toxicity at effective doses: aromatic polycyclic diones hypericin and pseudohypericin.

Cited by 401 publications

References 26 publications

Roles of Oxygen and Photoinduced Acidification in the Light-Dependent Antiviral Activity of Hypocrellin A

Roles of Oxygen and Photoinduced Acidification in the Light-Dependent Antiviral Activity of Hypocrellin A

Evaluation of the Light-Sensitive Cytotoxicity of Hypericum perforatum Extracts, Fractions, and Pure Compounds

Seco -pregnane steroids target the subgenomic RNA of alphavirus-like RNA viruses

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