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

Maria J P van Dongen; Rameshwar U Kadam; Jarek Juraszek; Edward Lawson; Boerries Brandenburg; Frederike Schmitz; Wim B G Schepens; Bart Stoops; Harry A van Diepen; Mandy Jongeneelen; Chan Tang; Jan Vermond; Alida van Eijgen-Obregoso Real; Sven Blokland; Divita Garg; Wenli Yu; Wouter Goutier; Ellen Lanckacker; Jaco M Klap; Daniëlle C G Peeters; Jin Wu; Christophe Buyck; Tim H M Jonckers; Dirk Roymans; Peter Roevens; Ronald Vogels; Wouter Koudstaal; Robert H E Friesen; Pierre Raboisson; Dashyant Dhanak; Jaap Goudsmit; Ian A Wilson

doi:10.1126/science.aar6221

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

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

Authors

Maria J P van Dongen^#^{1

2}, Rameshwar U Kadam^#³, Jarek Juraszek⁴, Edward Lawson⁵, Boerries Brandenburg^{4

6}, Frederike Schmitz⁴, Wim B G Schepens², Bart Stoops², Harry A van Diepen⁴, Mandy Jongeneelen^{4

6}, Chan Tang^{4

6}, Jan Vermond⁴, Alida van Eijgen-Obregoso Real⁴, Sven Blokland^{4

6}, Divita Garg⁷, Wenli Yu³, Wouter Goutier⁴, Ellen Lanckacker⁸, Jaco M Klap⁴, Daniëlle C G Peeters², Jin Wu⁸, Christophe Buyck², Tim H M Jonckers⁸, Dirk Roymans⁸, Peter Roevens², Ronald Vogels^{4

6}, Wouter Koudstaal⁴, Robert H E Friesen⁴, Pierre Raboisson⁸, Dashyant Dhanak^{2

5}, Jaap Goudsmit^{4

9}, Ian A Wilson^{10

11}

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Administration, Oral
Animals
Antibodies, Neutralizing / chemistry*
Biomimetic Materials / administration & dosage
Biomimetic Materials / pharmacokinetics
Biomimetic Materials / pharmacology*
Bronchi / virology
Cells, Cultured
Dogs
Hemagglutinin Glycoproteins, Influenza Virus / genetics
Hemagglutinin Glycoproteins, Influenza Virus / metabolism
Humans
Influenza A Virus, H1N1 Subtype / drug effects*
Influenza, Human / prevention & control*
Madin Darby Canine Kidney Cells
Mice
Piperazines / administration & dosage
Piperazines / pharmacokinetics
Piperazines / pharmacology*
Pyridines / administration & dosage
Pyridines / pharmacokinetics
Pyridines / pharmacology*
Respiratory Mucosa / virology
Tetrazoles / administration & dosage
Tetrazoles / pharmacokinetics
Tetrazoles / pharmacology*
Viral Fusion Protein Inhibitors / administration & dosage
Viral Fusion Protein Inhibitors / pharmacokinetics
Viral Fusion Protein Inhibitors / pharmacology*
Virus Internalization / drug effects*

Substances

Antibodies, Neutralizing
H1N1 virus hemagglutinin
Hemagglutinin Glycoproteins, Influenza Virus
JNJ4796
Piperazines
Pyridines
Tetrazoles
Viral Fusion Protein Inhibitors
hemagglutinin, avian influenza A virus

Abstract

Publication types

MeSH terms

Substances

Grants and funding