Lack of quantitative correlation between inhibition of replication of rhinoviruses by an antiviral drug and their stabilization

Andries, Koen; Dewindt, B.; Snoeks, Jos; Willebrords, R.

doi:10.1007/bf01311037

Cited by 28 publications

(18 citation statements)

References 25 publications

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“…Thus there was no correlation between the sensitivities of the different strains to the two compounds, or between the MIC and MSC46 values of the individual strains. A similar lack of quantitative correlation between inhibition of replication and thermal stabilization has been reported for the interaction of rhinoviruses with capsid-binding compounds (Andries et al, 1989), suggesting that factors other than stabilization contribute to the inhibition of replication of both polioviruses and rhinoviruses. The present report illustrates the possible use of antiviral compounds to protect thermolabile antigens in parenteral inactivated vaccine preparations.…”

Section: Discussionsupporting

confidence: 56%

“…In rhinoviruses, several WIN compounds and R 61837, the prototype of the pyridazinamine derivatives, have been shown to bind into a hydrophobic pocket located at the base of the 'canyon', within the fl-barrel of capsid protein VP1 (Smith et al, 1986;Chapman et al, 1991). Antipicornavirus compounds generally stabilize susceptible serotypes of rhino-, echo-and polioviruses against inactivation by heat, or by acid or alkaline pH (reviewed by Andries et al, 1989); in particular, WIN 51711 increases the immunogenicity of polio virions in mice and stabilizes procapsids up to 42 °C (Rombaut et al, 1990b).…”

Section: Introductionmentioning

confidence: 99%

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A comparison of WIN 51711 and R 78206 as stabilizers of poliovirus virions and procapsids

Rombaut

Andries

Boeyé

1991

Journal of General Virology

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The thermal denaturation of poliovirus virions and procapsids in the 42 to 48 °C range was studied using N-and H-specific monocional antibodies. The half-life of the N antigen of Mahoney and Sabin 1 virions was extended 50-to 250-fold by either 10 ~tM WIN 51711 or R 78206. The minimum concentrations required for full stabilization at 46 °C (1-0 ~tM for WIN 51711, 0-2 g~,l for R 78206) were independent of the strain or serotype of the virus; 30 to 60 molecules of stabilizer per virion were required for full protection. R 78206 was the most efficient stabilizer of Mahoney procapsids; the half-life of the N-specific epitopes of these particles at 44 *C was extended from less than 1 min to 1 day.

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Section: Discussionsupporting

confidence: 56%

Section: Introductionmentioning

confidence: 99%

A comparison of WIN 51711 and R 78206 as stabilizers of poliovirus virions and procapsids

Rombaut

Andries

Boeyé

1991

Journal of General Virology

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“…Note, however, that the most effective stabilizers of the capsid at high temperature (those with the highest ET 50 values) were the least effective at neutralization of infection (i.e., requiring the highest VHH concentration for neutralization). An analogous lack of a quantitative correlation between the stabilizing and neutralizing properties of an antiviral drug was previously described for the compound R61837 against rhinoviruses (42). Several factors could account for the lack of correlation, including the ability of the VHH to inhibit cell attachment of the virus, the ability to shift from low-affinity to high-affinity binding, and the ability to undergo the 135S transition.…”

Section: Formation Of Intermediate Virus Particlesmentioning

confidence: 99%

Mechanism of Action and Capsid-Stabilizing Properties of VHHs with an In Vitro Antipolioviral Activity

Schotte

Strauß

Thys

et al. 2014

J Virol

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Previously, we reported on the in vitro antiviral activity of single-domain antibody fragments (VHHs) directed against poliovirus type 1. Five VHHs were found to neutralize poliovirus type 1 in an in vitro setting and showed 50% effective concentrations (EC 50 s) in the nanomolar range. In the present study, we further investigated the mechanism of action of these VHHs. All five VHHs interfere at multiple levels of the viral replication cycle, as they interfere both with attachment of the virus to cells and with viral uncoating. The latter effect is consistent with their ability to stabilize the poliovirus capsid, as observed in a ThermoFluor thermal shift assay, in which the virus is gradually heated and the temperature causing 50% of the RNA to be released from the capsid is determined, either in the presence or in the absence of the VHHs. The VHH-capsid interactions were also seen to induce aggregation of the virus-VHH complexes. However, this observation cannot yet be linked to their mechanism of action. Cryo-electron microscopy (cryo-EM) reconstructions of two VHHs in complex with poliovirus type 1 show no conformational changes of the capsid to explain this aggregation. On the other hand, these reconstructions do show that the binding sites of VHHs PVSP6A and PVSP29F overlap the binding site for the poliovirus receptor (CD155/PVR) and span interfaces that are altered during receptor-induced conformational changes associated with cell entry. This may explain the interference at the level of cell attachment of the virus as well as their effect on uncoating. IMPORTANCEThe study describes the mechanism of neutralization and the capsid-stabilizing activity of five single-domain antibody fragments (VHHs) that have an in vitro neutralizing activity against poliovirus type 1. The results show that the VHHs interfere at multiple levels of the viral replication cycle (cell attachment and viral uncoating). These mechanisms are possibly shared by some conventional antibodies and may therefore provide some insight into the natural immune responses. Since the binding sites of two VHHs studied by cryo-EM are very similar to that of the receptor, the VHHs can be used as probes to study the authentic virus-cell interaction. The structures and conclusions in this study are original and raise interesting findings regarding virus-receptor interactions and the order of key events early in infection.

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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

119

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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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Lack of quantitative correlation between inhibition of replication of rhinoviruses by an antiviral drug and their stabilization

Cited by 28 publications

References 25 publications

A comparison of WIN 51711 and R 78206 as stabilizers of poliovirus virions and procapsids

A comparison of WIN 51711 and R 78206 as stabilizers of poliovirus virions and procapsids

Mechanism of Action and Capsid-Stabilizing Properties of VHHs with an In Vitro Antipolioviral Activity

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

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