Comparative studies on the antirhinovirus activity and the mode of action of the rhinovirus capsid binding agents, chalcone amides

Ninomiya, Yasuyuki; Shimma, Nobuo; Ishitsuka, Hideo

doi:10.1016/0166-3542(90)90022-y

Cited by 52 publications

(36 citation statements)

References 13 publications

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“…All of them are supposed to exert their antiviral activity by binding to virions, inducing conformational and flexibility changes in the capsid proteins and thus inhibiting the adsorption and/or uncoating event of the replication cycle (21). Drug-resistant mutants raised against some of these compounds usually exhibit cross-resistance to others, strongly suggesting a similar mode of action and a sharing of binding sites (3,17,18). Few of the compounds mentioned have been advanced to in vivo studies.…”

Section: Methodsmentioning

confidence: 99%

In vitro activity of pirodavir (R 77975), a substituted phenoxy-pyridazinamine with broad-spectrum antipicornaviral activity

Andries

Dewindt

Snoeks

et al. 1992

Antimicrob Agents Chemother

117

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Pirodavir (R 77975) is the prototype of a novel class of broad-spectrum antipicornavirus compounds. Although its predecessor, R 61837, a substituted phenyl-pyridazinamine, was effective in inhibiting 80% of 100 serotypes tested (EC.) at concentrations above 32 ,ug/ml, pirodavir inhibits the same percentage of viruses at 0.064 ,ug/ml. Whereas R 61837 was active almost exclusively against rhinovirus serotypes of antiviral group B, pirodavir is broad spectrum in that it is highly active against both group A and group B rhinovirus serotypes.Pirodavir is also effective in inhibiting 16 enteroviruses, with an ECgo of 1.3 ,ug/ml. Susceptible rhinovirus serotypes were rendered noninfectious by direct contact with the antiviral compound. Their infectivity was not restored by dilution of virus-drug complexes, but was regained by organic solvent extraction of the compound for most serotypes. Neutralized viruses became stabilized to acid and heat, strongly suggesting a direct interaction of the compounds with viral capsid proteins. Mutants resistant to R 61837 (up to 85 times the MIC) were shown to bear some cross-resistance (up to 23 times the MIC) to the new compound, indicating that pirodavir also binds into the hydrophobic pocket beneath the canyon floor of rhinoviruses. Pirodavir acts at an early stage of the viral replication cycle (up to 40 min after infection) and reduces the yield of selected rhinoviruses 1,000-to 100,000-fold in a single round of replication. The mode of action appears to be serotype specific, since pirodavir was able to inhibit the adsorption of human rhinovirus 9 but not that of human rhinovirus 1A. Pirodavir is a novel capsid-binding antipicornavirus agent with potent in vitro activity against both group A and group B rhinovirus serotypes.

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Section: Methodsmentioning

confidence: 99%

In vitro activity of pirodavir (R 77975), a substituted phenoxy-pyridazinamine with broad-spectrum antipicornaviral activity

Andries

Dewindt

Snoeks

et al. 1992

Antimicrob Agents Chemother

117

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“…In fact, pronounced antiviral activity has been reported in several species of the genus Euphorbia, against polio, coxsackie, and rhinoviruses (Vlietinck et al 1986, 1995, Ninomiya et al 1990, Unander et al 1995. Additionally, antitumour activity against sarcoma 180 ascites, leukemia in mice, and cytotoxic activity against certain cancer cell lines has also been observed (Itokawa et al 1989, Wu et al 1991, Fatope et al 1996.…”

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confidence: 99%

Cytotoxic and Antiviral Activities of Colombian Medicinal Plant Extracts of the Euphorbia genus

Betancur‐Galvis

Morales²,

Forero

et al. 2002

Mem. Inst. Oswaldo Cruz

150

104

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Several species of the genus Euphorbia (Euphorbiaceae) have been tested for their efficiency as antiviral and antitumour agents, partly based on information concerning plants that have traditionally been used as medication to treat various human diseases (Bernal & Correa 1990, Unander et al. 1995. In fact, pronounced antiviral activity has been reported in several species of the genus Euphorbia, against polio, coxsackie, and rhinoviruses (Vlietinck et al. 1986, 1995, Ninomiya et al. 1990, Unander et al. 1995. Additionally, antitumour activity against sarcoma 180 ascites, leukemia in mice, and cytotoxic activity against certain cancer cell lines has also been observed (Itokawa et al. 1989, Wu et al. 1991, Fatope et al. 1996.There seems to be increasing possibility of finding biological activity among plants with recorded medicinal uses rather than from plants randomly selected (Unander et al. 1995, Cordell 1995. Furthermore, selection of plants gives better criteria for screening programs especially in its initial phases, compared to the screening of compounds isolated and/or purified from natural products (Kusumoto et al. 1995, Cordell 1995, Baker et al. 1995.Finally, the strategy for research and in vitro evaluation of biological activity of natural products, has changed in the past few years. One of the recent developments is the highly automated bioassay screening method based on colorimetric assays, that quantify the proliferation of cell cultures (Mosmann 1983, Denizot & Lang 1986). These techniques, considered rapid and inexpensive for the evaluation of antitumour (Carmichael et al. 1987, Rubinstein et al. 1990) and antiviral activity (Weislow et al. 1989) of a large number of natural products, have also permitted the isolation and purification of biologically active principles (Cordell 1995, Baker et al. 1995.The objective of our work was to evaluate, using colorimetric assays, the in vitro antiherpetic and cytotoxic activity of some Euphorbia species that are known in Colombia, to have traditional medical uses against skin infections such as ulcers, warts, cancers, tumors, and possibly diseases of viral origin (Garcia-Barriga 1974, Perez 1975, Vasquez 1982, Bernal & Correa 1990, Piñeros et al. 1992. MATERIALS AND METHODSPlant collection -The species were collected in different municipalities of the Department of Antioquia and deposited in the herbarium of the University of Antioquia, Medellín, Colombia. E. cotinifolia, was collected in Girardota, at a mean altitude of 350 m; a voucher specimen was deposited under the number HUA 115472. E. cestrifolia was collected in Guarne, at a mean altitude of 2,000 m; a voucher specimen was deposited under the number HUA 95065. E. tirucalli, E. arenaria, and E. pulcherrima were collected in Medellín, at a mean altitude of 450 m; voucher specimens were deposited under the numbers RC11383, HUA 55275, RC11384, respectively. The species E. heterophyla, E. cyatophora, E. graminea, E. cf. cotinifolia and Euphorbia sp. were collected in San Jerónimo, at a mean altitude of...

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“…Ro 09-0410 is a chalcone capsid inhibitor that acts by a mechanism of action similar to that for pleconaril, binding to the same pocket in the VP1 protein. Ro 09-0410-resistant viruses are cross-resistant to pleconaril-class compounds (1,7,29). In the study, the drugresistant virus produced illness in one-half as many volunteers as the wild-type virus and infection in about one-third as many volunteers as the wild-type virus.…”

Section: Discussionmentioning

confidence: 99%

Relationship of Pleconaril Susceptibility and Clinical Outcomes in Treatment of Common Colds Caused by Rhinoviruses

Pevear¹,

Hayden

Demenczuk³

et al. 2005

Antimicrob Agents Chemother

100

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Pleconaril, a specific inhibitor of human picornaviruses, showed therapeutic efficacy against communityacquired colds caused by rhinoviruses in two placebo-controlled trials. Virological assessments were conducted during these trails, including virus culture and drug susceptibility testing. Nasal mucus samples collected from the enrolled patients were tested for the presence of picornavirus by reverse transcriptase PCR and culture. In total, 827 baseline nasal mucus samples were positive by virus culture (420 in the placebo group and 407 in the pleconaril group). Pleconaril treatment was associated with a more rapid loss of culturable virus. By study day 3, the number of samples positive by culture fell to 282 for the placebo-treated subjects and 202 for the pleconaril-treated subjects (P < 0.0001); and by day 6, the number of samples in the two groups positive by culture fell to 196 and 165, respectively (P ‫؍‬ 0.07). The clinical benefit correlated strongly with the pleconaril susceptibility of the baseline virus isolate. Pleconaril-treated subjects infected with the more highly susceptible viruses (50% effective concentration < 0.38 g/ml) experienced a median 1.9-to 3.9-day reduction in symptom duration compared with that for the placebo-treated subjects. By contrast, subjects whose baseline virus isolate susceptibility was >0.38 g/ml did not benefit from pleconaril treatment. These results indicate that the magnitude of symptomatic improvement in pleconaril-treated subjects with community-acquired colds is related to the drug susceptibility of the infecting virus, clearly linking the antiviral effects of the drug to clinical efficacy. Postbaseline virus isolates with reduced susceptibility or full resistance to pleconaril were recovered from 10.7% and 2.7% of drug-treated subjects, respectively. These patients shed low levels of virus and had no unusual clinical outcomes. Nevertheless, studies on the biologic properties and transmissibility of these variant viruses are warranted.

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Comparative studies on the antirhinovirus activity and the mode of action of the rhinovirus capsid binding agents, chalcone amides

Cited by 52 publications

References 13 publications

In vitro activity of pirodavir (R 77975), a substituted phenoxy-pyridazinamine with broad-spectrum antipicornaviral activity

In vitro activity of pirodavir (R 77975), a substituted phenoxy-pyridazinamine with broad-spectrum antipicornaviral activity

Cytotoxic and Antiviral Activities of Colombian Medicinal Plant Extracts of the Euphorbia genus

Relationship of Pleconaril Susceptibility and Clinical Outcomes in Treatment of Common Colds Caused by Rhinoviruses

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