Identification of a novel HA conformational change inhibitor of human influenza virus

Yoshimoto, Jun; Kakui, Mayumi; Iwasaki, H.; Fujiwara, Tamio; Sugimoto, H.; Hattori, Naohiko

doi:10.1007/s007050050552

Cited by 65 publications

(50 citation statements)

References 20 publications

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“…Hence, the available data are consistent with the mechanism of action for 4c and its congeners being the inhibition of HA protein-mediated membrane fusion. Several classes of small molecules that inhibit influenza virus fusion have been reported previously (2,5,30,49). While most of these compounds inhibit the acid-induced conformational change, diiodofluorescein was shown to act in an irreversible manner by premature triggering of this HA conformational change (12).…”

Section: Vol 84 2010 Novel Inhibitors Of Influenza Virus Fusion 4285mentioning

confidence: 99%

“…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.…”

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confidence: 99%

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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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Section: Vol 84 2010 Novel Inhibitors Of Influenza Virus Fusion 4285mentioning

confidence: 99%

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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“…Trypsin protection assay (TPA). Evaluation of the protective effects of the compounds on the trypsin digestion of HA was done as previously described (31). Briefly, 10 l of influenza A/WSN/33 [H1N1] viruses or of FA-583-or FA-617-associated mutant viruses (10 7 PFU) was incubated in the absence or presence of compounds for 15 min at 37°C and the reaction mixture was adjusted with 0.1 M acetate buffer (pH 4.8) to a final pH of 5.0.…”

Section: Methodsmentioning

confidence: 99%

Identification of Novel Fusion Inhibitors of Influenza A Virus by Chemical Genetics

Lai

Cheung

Yang

et al. 2016

J Virol

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A previous screening of more than 50,000 compounds led to the identification of a pool of bioactive small molecules with inhibitory effect on the influenza A virus. One of these compounds, now widely known as nucleozin, is a small molecule that targets the influenza A virus nucleoprotein. Here we identify and characterize two structurally different novel fusion inhibitors of the influenza A virus group 1 hemagglutinin (HA), FA-583 and FA-617, with low nanomolar activities. Escape mutants that are highly resistant to each of these compounds were generated, and both were found to carry mutations localized in close proximity to the B-loop of the hemagglutinin 2 protein, which plays a crucial role in the virion-host cell fusion process. Recombinant virus, generated through reverse genetics, confirmed the resistance phenotype. In addition, the proposed binding pockets predicted by molecular docking studies are in accordance with the resistance-bearing mutation sites. We show through mechanistic studies that FA-583 and FA-617 act as fusion inhibitors by prohibiting the low-pH-induced conformational change of hemagglutinin. Our study has offered concrete biological and mechanistic explorations for the strategic development of novel fusion inhibitors of influenza A viruses. IMPORTANCE Here we report two structurally distinctive novel fusion inhibitors of influenza

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“…Outras moléculas, como 25 (Figura 25), também inibiram a replicação do vírus influenza através deste mecanismo 78,79 . Um exemplo mais recente é a estachiflina (26), um derivado sesquiterpênico isolado de fungos do gênero Stachbotrys e que tem apresentado atividade inibitória da hemaglutinina viral 80,81 . Pesquisas em bibliotecas de compostos químicos levaram à identificação de 27, que inibiu o processo de infecção causado por subtipos da hemaglutinina do vírus influenza.…”

Section: Outros Tipos De Inibidoresunclassified

Ácidos siálicos: da compreensão do seu envolvimento em processos biológicos ao desenvolvimento de fármacos contra o agente etiológico da gripe

Fátima¹,

Baptistella²,

Pilli³

et al. 2005

Quím. Nova

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Recebido em 4/2/04; aceito em 13/7/04; publicado na web em 23/11/04 SIALIC ACIDS -FROM THE COMPREHENSION OF THEIR INVOLVEMENT IN BIOLOGICAL PROCESSES TO ANTIINFLUENZA DRUG DESIGN. Sialic acids are nine-carbon carbohydrates that occur widely in nature and occupy the terminal portions of some glycoproteins and glycolipids of cell membranes. These carbohydrates are closely involved in cell-cell interactions and in processes such as microbial infection, inflammation, etc. Studies on the participation of sialic acids in biological processes have provided comprehension about their role in the infection by the influenza virus, the causal agent of flu. In this article, we present an overview of the importance of sialic acids in the influenza virus infection and how the knowledge of their involvement in this process has allowed the development of selective and efficient drugs against the virus.Keywords: sialic acid; flu and antiinfluenza drugs. INTRODUÇÃONão há vida sem célula. E a exemplo da própria vida, que tanta diversidade apresenta, variam as formas e funções das células. As células são as unidades estruturais e funcionais de todos os organismos e é possível reconhecer, em sua hierarquia estrutural, alguns níveis de complexidade, como aqueles presentes, por exemplo, em uma célula vegetal: o nível 3 onde se incluem complexos supramoleculares (cromossomo, membrana plasmática, parede celular, etc); o nível 2 representado por macromoléculas (DNA, proteínas, celulose, etc) e o nível 1 compreendendo as unidades monoméricas, como nucleotídeos, aminoácidos, carboidratos, etc 1-3 (Figura 1).A membrana plasmática, presente em células de todas as espécies, define a periferia da célula, separando o seu conteúdo da circunvizinhança. Ela serve como uma barreira de permeabilidade, que permite à célula manter uma composição citoplasmática e é composta de grande número de moléculas de lipídios e proteínas que se mantêm juntas principalmente por interações hidrofóbicas, formando uma bicamada lipídica fina, resistente e flexível, em volta da célula 1-3 . Algumas proteínas presentes na membrana celular permitem a passagem de certos íons e moléculas (proteínas transportadoras). Outras proteí-nas exercem o papel de receptores, transmitindo o sinal do exterior para o interior da célula. Há ainda proteínas que funcionam como enzimas, participando de reações que ocorrem em membranas.

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Identification of a novel HA conformational change inhibitor of human influenza virus

Cited by 65 publications

References 20 publications

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

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

Identification of Novel Fusion Inhibitors of Influenza A Virus by Chemical Genetics

Ácidos siálicos: da compreensão do seu envolvimento em processos biológicos ao desenvolvimento de fármacos contra o agente etiológico da gripe

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