A small-molecule fusion inhibitor of influenza virus is orally active in mice.
Administration, Oral
Animals
Antibodies, Neutralizing
/ chemistry
Biomimetic Materials
/ administration & dosage
Bronchi
/ virology
Cells, Cultured
Dogs
Hemagglutinin Glycoproteins, Influenza Virus
/ genetics
Humans
Influenza A Virus, H1N1 Subtype
/ drug effects
Influenza, Human
/ prevention & control
Madin Darby Canine Kidney Cells
Mice
Piperazines
/ administration & dosage
Pyridines
/ administration & dosage
Respiratory Mucosa
/ virology
Tetrazoles
/ administration & dosage
Viral Fusion Protein Inhibitors
/ administration & dosage
Virus Internalization
/ drug effects
Journal
Science (New York, N.Y.)
ISSN: 1095-9203
Titre abrégé: Science
Pays: United States
ID NLM: 0404511
Informations de publication
Date de publication:
08 03 2019
08 03 2019
Historique:
received:
07
12
2017
revised:
09
10
2018
accepted:
29
01
2019
entrez:
9
3
2019
pubmed:
9
3
2019
medline:
20
8
2019
Statut:
ppublish
Résumé
Recent characterization of broadly neutralizing antibodies (bnAbs) against influenza virus identified the conserved hemagglutinin (HA) stem as a target for development of universal vaccines and therapeutics. Although several stem bnAbs are being evaluated in clinical trials, antibodies are generally unsuited for oral delivery. Guided by structural knowledge of the interactions and mechanism of anti-stem bnAb CR6261, we selected and optimized small molecules that mimic the bnAb functionality. Our lead compound neutralizes influenza A group 1 viruses by inhibiting HA-mediated fusion in vitro, protects mice against lethal and sublethal influenza challenge after oral administration, and effectively neutralizes virus infection in reconstituted three-dimensional cell culture of fully differentiated human bronchial epithelial cells. Cocrystal structures with H1 and H5 HAs reveal that the lead compound recapitulates the bnAb hotspot interactions.
Identifiants
pubmed: 30846569
pii: 363/6431/eaar6221
doi: 10.1126/science.aar6221
pmc: PMC6457909
mid: NIHMS1016739
pii:
doi:
Substances chimiques
Antibodies, Neutralizing
0
H1N1 virus hemagglutinin
0
Hemagglutinin Glycoproteins, Influenza Virus
0
JNJ4796
0
Piperazines
0
Pyridines
0
Tetrazoles
0
Viral Fusion Protein Inhibitors
0
hemagglutinin, avian influenza A virus
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Subventions
Organisme : NIGMS NIH HHS
ID : P41 GM103393
Pays : United States
Organisme : NIAID NIH HHS
ID : R56 AI117675
Pays : United States
Organisme : NIAID NIH HHS
ID : R56 AI127371
Pays : United States
Informations de copyright
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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