A novel amino acid substitution at the receptor-binding site on the hemagglutinin of H3N2 influenza A viruses isolated from 6 cases with acute encephalopathy during the 1997–1998 season in Tokyo

1999 ◽  
Vol 144 (1) ◽  
pp. 147-155 ◽  
Author(s):  
S.-I. Mori ◽  
M. Nagashima ◽  
Y. Sasaki ◽  
K. Mori ◽  
Y. Tabei ◽  
...  
Keyword(s):  
Amino Acid ◽  
Binding Site ◽  
Receptor Binding ◽  
Amino Acid Substitution ◽  
Influenza A ◽  
Acute Encephalopathy ◽  
Influenza A Viruses ◽  
Receptor Binding Site ◽  
H3n2 Influenza

scholarly journals Avian Influenza A Viruses Differ from Human Viruses by Recognition of Sialyloligosaccharides and Gangliosides and by a Higher Conservation of the HA Receptor-Binding Site

Virology ◽  
1997 ◽  
Vol 233 (1) ◽  
pp. 224-234 ◽  
Author(s):  
M.N. Matrosovich ◽  
A.S. Gambaryan ◽  
S. Teneberg ◽  
V.E. Piskarev ◽  
S.S. Yamnikova ◽  
...  
Keyword(s):  
Avian Influenza ◽  
Binding Site ◽  
Receptor Binding ◽  
Influenza A ◽  
Influenza A Viruses ◽  
Receptor Binding Site ◽  
Human Viruses

scholarly journals Potent sialic acid inhibitors that target influenza A virus hemagglutinin

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yu-Jen Chang ◽  
Cheng-Yun Yeh ◽  
Ju-Chien Cheng ◽  
Yu-Qi Huang ◽  
Kai-Cheng Hsu ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Antiviral Activity ◽  
Binding Site ◽  
Influenza A Virus ◽  
Receptor Binding ◽  
Influenza A ◽  
The United States ◽  
Ligand Complex ◽  
Receptor Binding Site ◽  
Computational Strategy

AbstractEradicating influenza A virus (IAV) is difficult, due to its genetic drift and reassortment ability. As the infectious cycle is initiated by the influenza glycoprotein, hemagglutinin (HA), which mediates the binding of virions to terminal sialic acids moieties, HA is a tempting target of anti-influenza inhibitors. However, the complexity of the HA structure has prevented delineation of the structural characterization of the HA protein–ligand complex. Our computational strategy efficiently analyzed > 200,000 records of compounds held in the United States National Cancer Institute (NCI) database and identified potential HA inhibitors, by modeling the sialic acid (SA) receptor binding site (RBS) for the HA structure. Our modeling revealed that compound NSC85561 showed significant antiviral activity against the IAV H1N1 strain with EC50 values ranging from 2.31 to 2.53 µM and negligible cytotoxicity (CC50 > 700 µM). Using the NSC85561 compound as the template to generate 12 derivatives, robust bioassay results revealed the strongest antiviral efficacies with NSC47715 and NSC7223. Virtual screening clearly identified three SA receptor binding site inhibitors that were successfully validated in experimental data. Thus, our computational strategy has identified SA receptor binding site inhibitors against HA that show IAV-associated antiviral activity.

Nicotinic receptor binding site probed with unnatural amino acid incorporation in intact cells

Science ◽  
1995 ◽  
Vol 268 (5209) ◽  
pp. 439-442 ◽  
Author(s):  
M. Nowak ◽  
P. Kearney ◽  
Sampson ◽  
M. Saks ◽  
C. Labarca ◽  
...  
Keyword(s):  
Amino Acid ◽  
Binding Site ◽  
Receptor Binding ◽  
Nicotinic Receptor ◽  
Unnatural Amino Acid ◽  
Amino Acid Incorporation ◽  
Receptor Binding Site ◽  
Intact Cells ◽  
Acid Incorporation

scholarly journals Novel Mutations Evading Avian Immunity around the Receptor Binding Site of the Clade 2.3.2.1c Hemagglutinin Gene Reduce Viral Thermostability and Mammalian Pathogenicity

Viruses ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 923 ◽  
Author(s):  
An ◽  
Lee ◽  
Hong ◽  
Song ◽  
Kim ◽  
...  
Keyword(s):  
Binding Site ◽  
Receptor Binding ◽  
Mammalian Cells ◽  
Influenza A ◽  
Receptor Binding Site ◽  
Receptor Affinity ◽  
Replication Efficiency ◽  
Adaptive Mutations ◽  
H5n1 Avian Influenza ◽  
Clade 2.3.2.1C

Abstract: Since 2007, highly pathogenic clade 2.3.2 H5N1 avian influenza A (A(H5N1)) viruses have evolved to clade 2.3.2.1a, b, and c; currently only 2.3.2.1c A(H5N1) viruses circulate in wild birds and poultry. During antigenic evolution, clade 2.3.2.1a and c A(H5N1) viruses acquired both S144N and V223I mutations around the receptor binding site of hemagglutinin (HA), with S144N generating an N-glycosylation sequon. We introduced single or combined reverse mutations, N144S and/or I223V, into the HA gene of the clade 2.3.2.1c A(H5N1) virus and generated PR8-derived, 2 + 6 recombinant A(H5N1) viruses. When we compared replication efficiency in embryonated chicken eggs, mammalian cells, and mice, the recombinant virus containing both N144S and I223V mutations showed increased replication efficiency in avian and mammalian hosts and pathogenicity in mice. The N144S mutation significantly decreased avian receptor affinity and egg white inhibition, but not all mutations increased mammalian receptor affinity. Interestingly, the combined reverse mutations dramatically increased the thermostability of HA. Therefore, the adaptive mutations possibly acquired to evade avian immunity may decrease viral thermostability as well as mammalian pathogenicity.

scholarly journals Phenotypic Effects of Substitutions within the Receptor Binding Site of Highly Pathogenic Avian Influenza H5N1 Virus Observed during Human Infection

2020 ◽  
Vol 94 (13) ◽  
Author(s):  
Dirk Eggink ◽  
Monique Spronken ◽  
Roosmarijn van der Woude ◽  
Jocynthe Buzink ◽  
Frederik Broszeit ◽  
...  
Keyword(s):  
Amino Acid ◽  
Avian Influenza ◽  
Binding Site ◽  
Receptor Binding ◽  
Human Infection ◽  
Influenza Viruses ◽  
Receptor Specificity ◽  
Receptor Binding Site ◽  
Human Type ◽  
Human Infections

ABSTRACT Highly pathogenic avian influenza (HPAI) viruses are enzootic in wild birds and poultry and continue to cause human infections with high mortality. To date, more than 850 confirmed human cases of H5N1 virus infection have been reported, of which ∼60% were fatal. Global concern persists that these or similar avian influenza viruses will evolve into viruses that can transmit efficiently between humans, causing a severe influenza pandemic. It was shown previously that a change in receptor specificity is a hallmark for adaptation to humans and evolution toward a transmittable virus. Substantial genetic diversity was detected within the receptor binding site of hemagglutinin of HPAI A/H5N1 viruses, evolved during human infection, as detected by next-generation sequencing. Here, we investigated the functional impact of substitutions that were detected during these human infections. Upon rescue of 21 mutant viruses, most substitutions in the receptor binding site (RBS) resulted in viable virus, but virus replication, entry, and stability were often impeded. None of the tested substitutions individually resulted in a clear switch in receptor preference as measured with modified red blood cells and glycan arrays. Although several combinations of the substitutions can lead to human-type receptor specificity, accumulation of multiple amino acid substitutions within a single hemagglutinin during human infection is rare, thus reducing the risk of virus adaptation to humans. IMPORTANCE H5 viruses continue to be a threat for public health. Because these viruses are immunologically novel to humans, they could spark a pandemic when adapted to transmit between humans. Avian influenza viruses need several adaptive mutations to bind to human-type receptors, increase hemagglutinin (HA) stability, and replicate in human cells. However, knowledge on adaptive mutations during human infections is limited. A previous study showed substantial diversity within the receptor binding site of H5N1 during human infection. We therefore analyzed the observed amino acid changes phenotypically in a diverse set of assays, including virus replication, stability, and receptor specificity. None of the tested substitutions resulted in a clear step toward a human-adapted virus capable of aerosol transmission. It is notable that acquiring human-type receptor specificity needs multiple amino acid mutations, and that variability at key position 226 is not tolerated, reducing the risk of them being acquired naturally.

Phylogenetic, molecular and drug-sensitivity analysis of HA and NA genes of human H3N2 influenza A viruses in Guangdong, China, 2007–2011

2012 ◽  
Vol 141 (5) ◽  
pp. 1061-1069 ◽  
Author(s):  
P. HUANG ◽  
L.-J. LIANG ◽  
N.-M. HOU ◽  
X. ZHANG ◽  
W.-Z. SU ◽  
...  
Keyword(s):  
Influenza A ◽  
Haemagglutination Inhibition ◽  
World Health ◽  
Public Health Issue ◽  
Influenza A Viruses ◽  
Receptor Binding Site ◽  
H3n2 Influenza ◽  
Health Organization ◽  
Influenza Outbreaks ◽  
Ha1 Gene

SUMMARYAnnual H3N2 subtype influenza outbreaks in Guangdong, China are a severe public health issue and require ongoing monitoring of emerging viral variants. The variation and evolution of haemagglutinin (HA) and neuraminidase (NA) genes of influenza isolates from Guangdong during 2007–2011 and others from GenBank were analysed using Lasergene 7.1 and MEGA 5.05, and serological analysis of antigens was determined by haemagglutination inhibition (HI). Susceptibility to antiviral drugs was correlated with genetic mutations. Phylogenetic analysis and alignment of HA and NA genes were performed on 18 Guangdong isolates and 26 global reference strains. The non-synonymous (dN) evolutionary rate of HA1 was 3·13 times that of HA2. Compared with the A/Perth/16/2009 vaccine HA gene, homologies of Guangdong isolates were between 98·8–99·7% and 98·0–98·4% in 2009 and 2010, respectively. Amino-acid substitutions were found in five epitopes of HA1 from Guangdong isolates between 2007 and 2011, especially in epitopes B (N160K) and D (K174R/N). The K189E/N/Q and T228A mutations in the receptor-binding site (RBS) occurred in the 2010 strains, which affected the antigenicity of HA1. The antigenicity of the epidemic H3N2 isolates in 2010 was somewhat different from that of A/Perth/16/2009. The Guangdong H3N2 isolates were determined to be oseltamivir-resistant with IC50 of 0·396±0·085 nmol/l (n=17) and zanamivir-resistant with IC50 of 0·477±0·149 nmol/l (n=18). Variations were present in epitopes B and D, two sites in the RBS and two glycosylation sites in the Guangdong H3N2 HA1 gene. The majority of the Guangdong H3N2 isolates were sensitive to oseltamivir and zanamivir. Compared to the World Health Organization 2012 vaccine strains, Guangdong H3N2 strains varied genetically and antigenically to some degree.

scholarly journals Substitutions near the Hemagglutinin Receptor-Binding Site Determine the Antigenic Evolution of Influenza A H3N2 Viruses in U.S. Swine

2014 ◽  
Vol 88 (9) ◽  
pp. 4752-4763 ◽  
Author(s):  
N. S. Lewis ◽  
T. K. Anderson ◽  
P. Kitikoon ◽  
E. Skepner ◽  
D. F. Burke ◽  
...  
Keyword(s):  
Binding Site ◽  
Receptor Binding ◽  
Influenza A ◽  
Receptor Binding Site ◽  
Antigenic Evolution

scholarly journals Correction for Koel et al., Antigenic Variation of Clade 2.1 H5N1 Virus Is Determined by a Few Amino Acid Substitutions Immediately Adjacent to the Receptor Binding Site

mBio ◽  
2014 ◽  
Vol 5 (4) ◽  
Author(s):  
Björn F. Koel ◽  
Stefan van der Vliet ◽  
David F. Burke ◽  
Theo M. Bestebroer ◽  
Eny E. Bharoto ◽  
...  
Keyword(s):  
Amino Acid ◽  
Binding Site ◽  
Receptor Binding ◽  
H5n1 Virus ◽  
Antigenic Variation ◽  
Amino Acid Substitutions ◽  
Receptor Binding Site
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