Inhibition of uncoating of fowl plague virus by l-adamantanamine hydrochloride

Kato, Naoya; Eggers, Hans J.

doi:10.1016/0042-6822(69)90281-5

Cited by 173 publications

(93 citation statements)

References 24 publications

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“…Both compounds inhibit virus uncoating (Kato & Eggers, 1969 ;Bukrinskaya et al, 1982). They slow down membrane fusion mediated by the low-pH form of haemagglutinin (Wharton et al, 1990Bron et al, 1993), a process believed to be coordinated with proton flux through the M2 ion channel into the virion during virus endocytosis (Hay, 1989 ;Wharton et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

Different modes of inhibition by adamantane amine derivatives and natural polyamines of the functionally reconstituted influenza virus M2 proton channel protein.

Lin

Hutter

Schroeder

1997

Journal of General Virology

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The influenza virus M2 protein, target of the antiviral drugs amantadine and rimantadine, forms a proton channel which functions during virus uncoating and maturation by modifying the pH in virions as well as in trans-Golgi vesicles. We studied the influence of different ionic gradients on the inhibition of the proton translocation activity of isolated, baculovirus-expressed M2 protein reconstituted into liposomes. Two distinct patterns of inhibition were observed. A group of amphiphilic amines including amantadine, cyclooctylamine and rimantadine inhibited M2 effectively in the presence of physiological Na M concentrations. The 10-fold greater activity of rimantadine over amantadine and the 100-fold stronger effect of cyclooctylamine compared to cyclopentylamine matched the relative activities in influenza virus-infected cells. A com-

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Section: Introductionmentioning

confidence: 99%

Different modes of inhibition by adamantane amine derivatives and natural polyamines of the functionally reconstituted influenza virus M2 proton channel protein.

Lin

Hutter

Schroeder

1997

Journal of General Virology

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“…The 96 amino acid polypeptides associate to form disulphide-linked homotetramers Holsinger & Lamb, 1991) which are modified by the addition of palmitate and phosphate (Sugrue et al, 1990b;Veit et al, 1991). As the target of the antiviral compounds amantadine and rimantadine (Hay et al, 1985) M2 was implicated in virus uncoating (Kato & Eggers, 1969;Bukrinskaya et al,, 1982;Wharton et al, 1990;Martin & Helenins, 1991). More recently, it has been proposed that during endocytosis the M2 ion channel is responsible for allowing the passage of protons from the acid endosome into the virion, thereby promoting a low pH-induced dissociation of the matrix protein from the nucleocapsid (Hay, 1989;Wharton et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

Functional reconstitution in lipid vesicles of influenza virus M2 protein expressed by baculovirus: evidence for proton transfer activity

Schroeder¹,

Ford²,

Wharton³

et al. 1994

Journal of General Virology

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The influenza virus M2 protein was expressed from a recombinant baculovirus in Spodoptera frugiperda Sf9 cells, purified and reconstituted into artificial membrane vesicles. The specific inhibitor amantadine overcame the toxic activity of the protein and boosted the rate of M2 synthesis by a factor of 10, allowing yields of about 1 mg of purified M2 protein per g of Sf9 cells. M2 protein expressed in this system was phosphorylated and palmitoylated and displayed properties similar to the authentic virus protein. Purified wild-type M2 protein and an amantadine-resistant mutant M2 (M26) with a deletion in the trans-membrane domain (amino acids 28 to 31) were incorporated into lipid vesicles, which were loaded with the fluorescent pH indicator pyranine. On imposition of an ionic gradient, M2 caused a decrease in intravesicular pH, which was susceptible to inhibition by 0.1 to 1 gM-rimantadine or N-ethylrimantadine. M26 behaved similarly but exhibited the expected drug resistance. These experiments indicate that isolated M2 functions as an ion channel and demonstrates in vitro M2-mediated proton translocation.

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“…The similarities in the single amino acid substitutions which confer drug resistance demonstrates the correspondence between the mechanisms of action in vivo and in vitro. In cell culture two stages in the replicative cycle have been shown to be susceptible to drug action: (i) an essential aspect of virus uncoating which appears to be distinct from membrane fusion per se (Kato and Eggers, 1969;Bukrinskaya et al, 1982;Wharton et al, 1990) and (ii) a feature important for virus maturation. Although susceptibility to the former action appears to be determined largely by the M gene (Lubeck et al, 1978;Hay et al, 1979), analyses of reassortant viruses showed that susceptibility of certain H5 and H7 viruses to the latter action is dependent also on properties of their haemagglutinins (Scholtissek and Faulkner, 1979;Hay and Zambon, 1984;Bean et al, 1989).…”

Section: Introductionmentioning

confidence: 99%

Specific structural alteration of the influenza haemagglutinin by amantadine.

Sugrue¹,

Bahadur²,

Zambon³

et al. 1990

The EMBO Journal

208

186

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Amantadine hydrochloride specifically blocks the release of virus particles from H7 influenza virus infected cells. This appears to be the direct consequence of an amantadine induced change in the haemagglutinin (HA) to its low pH conformation. The effect is indirect and mediated via interaction of the drug with the M2 protein since mutants altered in this component alone are insensitive to amantadine. The tining of drug action, some 15-20 min after synthesis, and its coincidence with proteolytic cleavage indicates that the modifications to HA occur late during transport but prior to insertion into the plasma membrane. Reversal by mM concentrations of amines and 0.1 /M monensin indicates that amantadine action causes a reduction in intravesicular pH which triggers the conformational change in HA. We conclude, therefore, that the function of MN inhibited by amantadine is involved in counteracting the acidity of vesicular compartments of the exocytic pathway in infected cells and is important in protecting the structural integrity of the acid-sensitive glycoprotein.

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Inhibition of uncoating of fowl plague virus by l-adamantanamine hydrochloride

Cited by 173 publications

References 24 publications

Different modes of inhibition by adamantane amine derivatives and natural polyamines of the functionally reconstituted influenza virus M2 proton channel protein.

Different modes of inhibition by adamantane amine derivatives and natural polyamines of the functionally reconstituted influenza virus M2 proton channel protein.

Functional reconstitution in lipid vesicles of influenza virus M2 protein expressed by baculovirus: evidence for proton transfer activity

Specific structural alteration of the influenza haemagglutinin by amantadine.

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