In vitro activity of R 61837, a new antirhinovirus compound

Andries, Koen; Dewindt, B.; Brabander, M. De; Stokbroekx, Raymond A.; Janssen, P. A. J.

doi:10.1007/bf01310997

Cited by 55 publications

(37 citation statements)

References 16 publications

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“…Multiple therapeutic approaches targeting HRV have been progressed into the clinic, including small-molecule capsid-binding inhibitors (pleconaril [11], pirodavir [1,14], and BTA798 [3]), a 3C protease inhibitor (rupintrivir [35]), and soluble ICAM-1 (45). Although several inhibitors showed a modest antiviral effect in early clinical trials, none have been approved for treatment.…”

mentioning

confidence: 99%

Infection and Propagation of Human Rhinovirus C in Human Airway Epithelial Cells

Hao¹,

Bernard²,

Patel³

et al. 2012

J Virol

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Human rhinovirus species C (HRV-C) was recently discovered using molecular diagnostic techniques and is associated with lower respiratory tract disease, particularly in children. HRV-C cannot be propagated in immortalized cell lines, and currently sinus organ culture is the only system described that is permissive to HRV-C infection ex vivo. However, the utility of organ culture for studying HRV-C biology is limited. Here, we report that a previously described HRV-C derived from an infectious cDNA, HRV-C15, infects and propagates in fully differentiated human airway epithelial cells but not in undifferentiated cells. We demonstrate that this differentiated epithelial cell culture system supports infection and replication of a second virus generated from a cDNA clone, HRV-C11. We show that HRV-C15 virions preferentially bind fully differentiated airway epithelial cells, suggesting that the block to replication in undifferentiated cells is at the step of viral entry. Consistent with previous reports, HRV-C15 utilizes a cellular receptor other than ICAM-1 or LDLR for infection of differentiated epithelial cells. Furthermore, we demonstrate that HRV-C15 replication can be inhibited by an HRV 3C protease inhibitor (rupintrivir) but not an HRV capsid inhibitor previously under clinical development (pleconaril). The HRV-C cell culture system described here provides a powerful tool for studying the biology of HRV-C and the discovery and development of HRV-C inhibitors.

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mentioning

confidence: 99%

Infection and Propagation of Human Rhinovirus C in Human Airway Epithelial Cells

Hao¹,

Bernard²,

Patel³

et al. 2012

J Virol

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“…The wide range of susceptibilities of different HRV sero- (2) and slightly different from those described for chalcone, dichloroflavan, and isoflavans, which can be removed from neutralized serotypes by organic-solvent extraction (10,17). A classical S-shaped dose-response curve between the extent of neutralization and the ratio of pirodavir concentration to MIC could be observed (Fig.…”

Section: Methodsmentioning

confidence: 90%

“…Pirodavir (R 77975) is a substituted phenoxy-pyridazinamine, distantly related to its predecessor, R 61837, a substituted phenyl-pyridazinamine (2) (Fig. 1).…”

Section: * Corresponding Authormentioning

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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“…The anti-ICAM-1 monoclonal antibody R6.5 was prepared and characterized as described previously (12,14). Pirodavir (3,17). Briefly, fragments were cut from the epithelial surface of the adenoid within 6 h after removal and were dissected to produce 2-mm3 explants.…”

Section: Methodsmentioning

confidence: 99%

In vitro studies of the antirhinovirus activity of soluble intercellular adhesion molecule-1

Arruda

Crump

Marlin

et al. 1992

Antimicrob Agents Chemother

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We studied the in vitro antirhinovirus activity of a soluble form of intercellular adhesion molecule-i (sICAM-1). sICAM-1 inhibited the cytopathic effect of 10 representative human rhinovirus (HRV) serotypes of the major receptor group with, 50%o effective concentrations (ECs.s) of 0.1 to 7.9 ,ug/ml. Cell type-dependent variation in the inhibitory activity of sICAM-1 was observed for two major receptor group serotypes in HeLa cells (EC50, >32 ,ug/ml), and no inhibitory effect was observed for two serotypes which use different cell receptors. Yield reduction assays showed that sICAM-1 inhibited the replication of HRV serotype in human adenoid explants in a concentration-dependent manner. No direct inactivation of infectivity of HRV-39 (EC50, 0.5 jLg/ml) was observed after incubation with sICAM-1 (32 jg/mi) for up to 24 h. Singlecycle-of-replication experiments with the addition of sICAM-1 at 10 pg/mI at different times showed that the inhibitory effect occurs only when sICAM-1 is added within 30 min after infection. In experiments in which absorption was carried out at 4°C and then a single cycle of replication incubation was carried out at 33°C, it was found that sICAM-1 at 10 jig/ml was inhibitory only when it was present during the absorption period. Our data show that sICAM-1 is inhibitory for representative major receptor group serotypes of HRV in two cell lines and human respiratory epithelium, that the interaction of sICAM-1 with HRV is readily reversible by dilution, and that the inhibitory effect of sICAM-1 on virus replication is present early in the infection cycle.The glycoprotein intercellular adhesion molecule type 1 (ICAM-1) has been identified as the cell receptor for the major receptor group of human rhinoviruses (HRVs), which includes approximately 90% of the numbered serotypes (7,14,15). ICAM-1, which is a member of the immunoglobulin superfamily, is a cell surface molecule which functions as a ligand for the lymphocyte function-associated antigen-1 and promotes interactions between leukocytes and a number of cell types (9). ICAM-1 is composed of five extracellular immunoglobulinlike domains, one transmembrane anchor, and an intracytoplasmic C-terminal domain (7,14). The primary site for the interaction of both lymphocyte functionassociated antigen-1 and HRV seems to be within domain 1 of ICAM-1 (13). HRV in cultures of established cell lines and explants of human respiratory epithelium and to assess the mechanism of antirhinovirus activity of sICAM-1. MATERIALS AND METHODSV'iruses, cells, and reagents. Laboratory-passaged stocks of

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In vitro activity of R 61837, a new antirhinovirus compound

Cited by 55 publications

References 16 publications

Infection and Propagation of Human Rhinovirus C in Human Airway Epithelial Cells

Infection and Propagation of Human Rhinovirus C in Human Airway Epithelial Cells

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

In vitro studies of the antirhinovirus activity of soluble intercellular adhesion molecule-1

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