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Science. 2019 Mar 8;363(6431). pii: eaar6221. doi: 10.1126/science.aar6221.

A small-molecule fusion inhibitor of influenza virus is orally active in mice.

Author information

1
Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, Archimedesweg 6, Leiden, Netherlands. mvandon@its.jnj.com wilson@scripps.edu.
2
Discovery Sciences, Janssen Research & Development, Turnhoutseweg 30, Beerse, Belgium.
3
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA.
4
Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, Archimedesweg 6, Leiden, Netherlands.
5
Discovery Sciences, Janssen Research & Development, 1400 McKean Rd., Spring House, PA, USA.
6
Janssen Infectious Diseases and Vaccines, Janssen Research & Development, Archimedesweg 4-6, Leiden, Netherlands.
7
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA.
8
Janssen Infectious Diseases and Vaccines, Janssen Research & Discovery, Turnhoutseweg 30, Beerse, Belgium.
9
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
10
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA. mvandon@its.jnj.com wilson@scripps.edu.
11
The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA.
#
Contributed equally

Abstract

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.

PMID:
30846569
PMCID:
PMC6457909
DOI:
10.1126/science.aar6221
[Indexed for MEDLINE]
Free PMC Article

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