Characteristics of arbidol-resistant mutants of influenza virus: Implications for the mechanism of anti-influenza action of arbidol

Ленева, И. А.; Russell, Rosemary; Boriskin, Yu. S.; Hay, Alan J.

doi:10.1016/j.antiviral.2008.10.009

Cited by 261 publications

(245 citation statements)

References 36 publications

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“…The structures were obtained by soaking apo crystals of H7/SH2 and H3/HK68 HAs with ∼2.5 mM Arbidol. Earlier studies that used mass spectroscopy and in silico modeling predicted that Arbidol would bind in a cavity along the threefold symmetry axis of the HA trimer and interact with the fusion peptide (22,25). However, the electron density maps clearly demonstrate that Arbidol binds further up the stem region, ∼16 Å from the fusion peptide, with three Arbidol sites per trimer ( Fig.…”

Section: Resultsmentioning

confidence: 95%

“…One major drawback of Arbidol is that a large dose must be administered to achieve peak plasma concentration and therapeutic efficacy. To understand the molecule mechanism for its broad-spectrum inhibition of influenza viruses, various in vitro assays have been reported (14,(22)(23)(24), From the reported K d s with H1, H2, H3, H4, and H5 HA strains, Arbidol binds with higher affinity to group 2 HAs (K d s = 5.6-7.9 μM) than to group 1 HAs (K d s = 18.8-44.3 μM) (23). Mechanistically, Arbidol has been shown to increase influenza virus HA stability and prevent the low pH-induced HA transition to its fusogenic state, thereby blocking infection at one of the two key steps in cell entry, i.e., at viral fusion.…”

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confidence: 99%

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Structural basis of influenza virus fusion inhibition by the antiviral drug Arbidol

Kadam

Wilson

2016

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

380

359

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The broad-spectrum antiviral drug Arbidol shows efficacy against influenza viruses by targeting the hemagglutinin (HA) fusion machinery. However, the structural basis of the mechanism underlying fusion inhibition by Arbidol has remained obscure, thereby hindering its further development as a specific and optimized influenza therapeutic. We determined crystal structures of Arbidol in complex with influenza virus HA from pandemic 1968 H3N2 and recent 2013 H7N9 viruses. Arbidol binds in a hydrophobic cavity in the HA trimer stem at the interface between two protomers. This cavity is distal to the conserved epitope targeted by broadly neutralizing stem antibodies and is ∼16 Å from the fusion peptide. Arbidol primarily makes hydrophobic interactions with the binding site but also induces some conformational rearrangements to form a network of inter-and intraprotomer salt bridges. By functioning as molecular glue, Arbidol stabilizes the prefusion conformation of HA that inhibits the large conformational rearrangements associated with membrane fusion in the low pH of the endosome. This unique binding mode compared with the small-molecule inhibitors of other class I fusion proteins enhances our understanding of how small molecules can function as fusion inhibitors and guides the development of broad-spectrum therapeutics against influenza virus.influenza virus | hemagglutinin | X-ray crystallography | Arbidol | fusion inhibitor

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Section: Resultsmentioning

confidence: 95%

mentioning

confidence: 99%

Structural basis of influenza virus fusion inhibition by the antiviral drug Arbidol

Kadam

Wilson

2016

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

380

359

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“…The latter is a sequence of hydrophobic amino acids located at the N terminus of the HA2 subunit, which is, in the prefusogenic conformation, sequestered in a pocket of ionizable residues at the monomer interface of the HA trimer (48). In order to exploit the HA protein as an antiviral target, several small-molecule inhibitors that block the acid-induced conformational change of HA have been identified (2,19,21,30,49). For many of these, development has been hindered by their subtype-dependent activities.…”

mentioning

confidence: 99%

Novel Inhibitors of Influenza Virus Fusion: Structure-Activity Relationship and Interaction with the Viral Hemagglutinin

Vanderlinden

Göktaş

Cesur

et al. 2010

J Virol

146

175

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Currently available drugs for the prevention and treatment of seasonal influenza virus infections are the M2 ion channel blockers (amantadine and rimantadine) and the neuraminidase (NA) inhibitors (oseltamivir and zanamivir) (9). The clinical usefulness of amantadine and rimantadine is limited due to the increasing incidence of adamantane-resistant viruses in the population (3, 11). Moreover, the M2 ion channel blockers inhibit only influenza A virus replication and are associated with neurological side effects. NA inhibitors are favored clinically, since they are effective against all NA subtypes, are well tolerated, and have a higher barrier for resistance (27). However, drug-resistant isolates have been detected in A/H3N2-and A/H5N1-infected patients receiving oseltamivir treatment (10, 16). Even more reason for concern is the recent and worldwide isolation of oseltamivir-resistant A/H1N1 mutants, even among untreated patients (17, 46). Oseltamivir and, to a lesser extent, zanamivir have been stockpiled as part of pandemic preparedness plans and form the cornerstone of the response to the recent outbreak of the swine flu A/H1N1 virus (39, 40). However, it is unclear whether these antivirals will be sufficient to deal with larger influenza epidemics, so there is an urgent need to develop antivirals that act on a novel influenza virus target.An attractive antiviral strategy is to block influenza virus entry into the host cell, a process in which the viral hemagglutinin (HA) plays a key role (42). HA is a trimeric envelope glycoprotein that contains two disulfide-linked polypeptide chains, HA1 and HA2. After attachment of the receptor binding domain in the HA1 subunit to sialic acid-containing cell surface glycans, the virion is internalized by endocytosis. The acidic pH of the endosome leads to an extensive and irreversible conformational change of the HA protein, resulting in exposure of the fusion peptide, which inserts into the endosomal target membrane of the host cell (18). After fusion of the viral and endosomal membranes, the viral ribonucleoproteins are released into the cytosol and transported into the nucleus, where replication occurs (6). Crystallographic studies have provided detailed insight into the processes of HA refolding and extrusion of the fusion peptide (4). The latter is a sequence of hydrophobic amino acids located at the N terminus of the HA2 subunit, which is, in the prefusogenic conformation, sequestered in a pocket of ionizable residues at the monomer interface of the HA trimer (48). In order to exploit the HA protein as an antiviral target, several small-molecule inhibitors that block the acid-induced conformational change of HA have been identified (2,19,21,30,49). For many of these, development has been hindered by their subtype-dependent activities. On the other hand, these diverse fusion inhibitors represent excellent tools to identify the HA amino acid residues involved in the fusion process and/or delineate the structural differences among HA subtypes (36). We report here the i...

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“…The predominant mode of 59 action for arbidol is based on its intercalation into membrane lipids and on the subsequent 60 inhibition of membrane fusion between the virus and the plasma membrane and also 61 between the virus and the endocytic vesicle membrane [9]. In influenza virus, arbidol was 62 observed to interact with virus hemagglutinin (HA); this interaction results in an increased 63 HA stability and prevents pH-induced HA transition to its fusogenic state [10]. In the case of 64 hepatitis C virus (HCV) arbidol interacts with HCV envelope protein to cause various degree 65 of fusion inhibition [11;12].…”

Section: Arthropod-borne Flaviviruses (Genus Flavivirusmentioning

confidence: 99%

Arbidol (Umifenovir): A Broad-spectrum Antiviral Drug that Inhibits Medically Important Arthropod-borne Flaviviruses

Haviernik

Štefánik

Fojtíková

et al. 2018

Preprint

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Characteristics of arbidol-resistant mutants of influenza virus: Implications for the mechanism of anti-influenza action of arbidol

Cited by 261 publications

References 36 publications

Structural basis of influenza virus fusion inhibition by the antiviral drug Arbidol

Structural basis of influenza virus fusion inhibition by the antiviral drug Arbidol

Novel Inhibitors of Influenza Virus Fusion: Structure-Activity Relationship and Interaction with the Viral Hemagglutinin

Arbidol (Umifenovir): A Broad-spectrum Antiviral Drug that Inhibits Medically Important Arthropod-borne Flaviviruses

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