Antibody 27F3 Broadly Targets Influenza A Group 1 and 2 Hemagglutinins through a Further Variation in VH1-69 Antibody Orientation on the HA Stem

Lang, Shanshan; Xie, Jia; Zhu, Xueyong; Wu, Nicholas C.; Lerner, Richard A.; Wilson, Ian A.

doi:10.1016/j.celrep.2017.08.084

Cited by 101 publications

(117 citation statements)

References 56 publications

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“…Furthermore, the exposure of the fusion peptide at the surface of prefusion S trimers (Walls et al, 2016a) and its conservation among CoVs indicate it might be an attractive target for broad inhibition of CoV entry. Major antigenic determinants of MHV and SARS-CoV S overlap with the fusion peptide region (Daniel et al, 1993;Zhang et al, 2004) and binding of neutralizing antibodies to this site could putatively prevent fusogenic conformational changes, as proposed for influenza virus hemagglutinin or HIV envelope (Corti et al, 2011;Kong et al, 2016;Lang et al, 2017). Finally, masking strain-specific antigenic regions via engineering of additional N-linked glycosylation sites, as implemented for the MERS-CoV domain B (Du et al, 2016), bears the promise of focusing the immune response on highly conserved epitopes and eliciting broadly neutralizing antibodies against CoVs.…”

Section: Resultsmentioning

confidence: 99%

Structural insights into coronavirus entry

Tortorici

Veesler

2019

Advances in Virus Research

765

720

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Coronaviruses (CoVs) have caused outbreaks of deadly pneumonia in humans since the beginning of the 21st century. The severe acute respiratory syndrome coronavirus (SARS-CoV) emerged in 2002 and was responsible for an epidemic that spread to five continents with a fatality rate of 10% before being contained in 2003 (with additional cases reported in 2004). The Middle-East respiratory syndrome coronavirus (MERS-CoV) emerged in the Arabian Peninsula in 2012 and has caused recurrent outbreaks in humans with a fatality rate of 35%. SARS-CoV and MERS-CoV are zoonotic viruses that crossed the species barrier using bats/palm civets and dromedary camels, respectively. No specific treatments or vaccines have been approved against any of the six human coronaviruses, highlighting the need to investigate the principles governing viral entry and cross-species transmission as well as to prepare for zoonotic outbreaks which are likely to occur due to the large reservoir of CoVs found in mammals and birds. Here, we review our understanding of the infection mechanism used by coronaviruses derived from recent structural and biochemical studies.

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Section: Resultsmentioning

confidence: 99%

Structural insights into coronavirus entry

Tortorici

Veesler

2019

Advances in Virus Research

765

720

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“…Baculovirus-expressed HA was prepared for the study as previously described (3,34,35). In brief, the HA ectodomain sequence was cloned into the pFastBac vector with an N-terminal gp67 secretion signal peptide, a C-terminal BirA biotinylation site, thrombin cleavage site, foldon trimerization domain, and His6 tag.…”

Section: Preparation Of H7 Hamentioning

confidence: 99%

Potent anti-influenza H7 human monoclonal antibody induces separation of hemagglutinin receptor binding head domains

Turner

Pallesen

Lang

et al. 2018

Preprint

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Seasonal influenza virus infections can cause significant morbidity and mortality, but the threat from emergence of a new pandemic influenza strain might have potentially even more devastating consequences. As such, there is intense interest in isolating and characterizing potent neutralizing antibodies that target the hemagglutinin (HA) viral surface glycoprotein. Here, we use cryo-electron microscopy to decipher the mechanism of action of a potent HA head-directed monoclonal antibody bound to an influenza H7 HA. The epitope of the antibody is not solvent accessible in the compact, pre-fusion conformation that typifies all HA structures to date.Instead, the antibody binds between HA head protomers to an epitope that must be partly or transiently exposed in the pre-fusion conformation. The "breathing" of the HA protomers is implied by the exposure of this epitope, which is consistent with metastability of class I fusion proteins. This structure likely therefore represents an early structural intermediate in the viral fusion process. Understanding the extent of transient exposure of conserved neutralizing epitopes also may lead to new opportunities to combat influenza that have not been appreciated previously. Author SummaryA transiently exposed epitope on influenza H7 hemagglutinin represents a new target for neutralizing antibodies.

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“…The final coordinates were validated using MolProbity (42). (43,44). 500 µM of F0045(S)/(R) in 0.5% DMSO were 2-fold serially diluted in 50 TCID50 virus diluent in triplicates and incubated with cells at 37 ºC for 72 hr in a 5% CO2 incubator.…”

Section: Crystallization and Structure Determination Of F0045(s)-h1/pmentioning

confidence: 99%

An influenza A hemagglutinin small-molecule fusion inhibitor identified by a new high-throughput fluorescence polarization screen

Yao

Kadam

Lee

et al. 2020

Preprint

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Influenza hemagglutinin (HA) glycoprotein is the primary surface antigen targeted by the host immune response and a focus for development of novel vaccines, broadly neutralizing antibodies (bnAbs) and therapeutics. HA enables viral entry into host cells via receptor binding and membrane fusion and is a validated target for drug discovery. However, to date, only a very few bona fide small molecules have been reported against the HA. To identity new antiviral lead candidates against the highly conserved fusion machinery in the HA stem, we synthesized a fluorescence-polarization probe based on a recently described neutralizing cyclic peptide P7 derived from the complementarity-determining region loops of human bnAbs FI6v3 and CR9114 against the HA stem. We then designed a robust binding assay compatible with highthroughput screening to identify molecules with low µM to nM affinity to influenza A group 1 HAs. Our simple, low-cost, and efficient in vitro assay was used to screen H1/Puerto Rico/8/1934 HA trimer against approximately 72,000 compounds. The crystal structure of H1/Puerto Rico/8/1934 HA in complex with our best hit compound F0045(S) confirmed that it binds to pockets in the HA stem similar to bnAbs FI6v3 and CR9114, cyclic peptide P7, and small molecule inhibitor JNJ4796. F0045 is enantioselective against a panel of group 1 HAs and F0045(S) exhibits in vitro neutralization activity against multiple H1N1 and H5N1 strains.Our assay, compound characterization, and small-molecule candidate should further stimulate the 2 discovery and development of new compounds with unique chemical scaffolds and enhanced influenza antiviral capabilities. Summary

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Antibody 27F3 Broadly Targets Influenza A Group 1 and 2 Hemagglutinins through a Further Variation in VH1-69 Antibody Orientation on the HA Stem

Cited by 101 publications

References 56 publications

Structural insights into coronavirus entry

Structural insights into coronavirus entry

Potent anti-influenza H7 human monoclonal antibody induces separation of hemagglutinin receptor binding head domains

An influenza A hemagglutinin small-molecule fusion inhibitor identified by a new high-throughput fluorescence polarization screen

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