دورية أكاديمية
أعرض في EDS

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

التفاصيل البيبلوغرافية
العنوان: A small-molecule fusion inhibitor of influenza virus is orally active in mice.
المؤلفون: van Dongen MJP; Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, Archimedesweg 6, Leiden, Netherlands. mvandon@its.jnj.com wilson@scripps.edu.; Discovery Sciences, Janssen Research & Development, Turnhoutseweg 30, Beerse, Belgium., Kadam RU; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA., Juraszek J; Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, Archimedesweg 6, Leiden, Netherlands., Lawson E; Discovery Sciences, Janssen Research & Development, 1400 McKean Rd., Spring House, PA, USA., Brandenburg B; Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, Archimedesweg 6, Leiden, Netherlands.; Janssen Infectious Diseases and Vaccines, Janssen Research & Development, Archimedesweg 4-6, Leiden, Netherlands., Schmitz F; Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, Archimedesweg 6, Leiden, Netherlands., Schepens WBG; Discovery Sciences, Janssen Research & Development, Turnhoutseweg 30, Beerse, Belgium., Stoops B; Discovery Sciences, Janssen Research & Development, Turnhoutseweg 30, Beerse, Belgium., van Diepen HA; Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, Archimedesweg 6, Leiden, Netherlands., Jongeneelen M; Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, Archimedesweg 6, Leiden, Netherlands.; Janssen Infectious Diseases and Vaccines, Janssen Research & Development, Archimedesweg 4-6, Leiden, Netherlands., Tang C; Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, Archimedesweg 6, Leiden, Netherlands.; Janssen Infectious Diseases and Vaccines, Janssen Research & Development, Archimedesweg 4-6, Leiden, Netherlands., Vermond J; Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, Archimedesweg 6, Leiden, Netherlands., van Eijgen-Obregoso Real A; Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, Archimedesweg 6, Leiden, Netherlands., Blokland S; Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, Archimedesweg 6, Leiden, Netherlands.; Janssen Infectious Diseases and Vaccines, Janssen Research & Development, Archimedesweg 4-6, Leiden, Netherlands., Garg D; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA., Yu W; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA., Goutier W; Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, Archimedesweg 6, Leiden, Netherlands., Lanckacker E; Janssen Infectious Diseases and Vaccines, Janssen Research & Discovery, Turnhoutseweg 30, Beerse, Belgium., Klap JM; Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, Archimedesweg 6, Leiden, Netherlands., Peeters DCG; Discovery Sciences, Janssen Research & Development, Turnhoutseweg 30, Beerse, Belgium., Wu J; Janssen Infectious Diseases and Vaccines, Janssen Research & Discovery, Turnhoutseweg 30, Beerse, Belgium., Buyck C; Discovery Sciences, Janssen Research & Development, Turnhoutseweg 30, Beerse, Belgium., Jonckers THM; Janssen Infectious Diseases and Vaccines, Janssen Research & Discovery, Turnhoutseweg 30, Beerse, Belgium., Roymans D; Janssen Infectious Diseases and Vaccines, Janssen Research & Discovery, Turnhoutseweg 30, Beerse, Belgium., Roevens P; Discovery Sciences, Janssen Research & Development, Turnhoutseweg 30, Beerse, Belgium., Vogels R; Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, Archimedesweg 6, Leiden, Netherlands.; Janssen Infectious Diseases and Vaccines, Janssen Research & Development, Archimedesweg 4-6, Leiden, Netherlands., Koudstaal W; Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, Archimedesweg 6, Leiden, Netherlands., Friesen RHE; Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, Archimedesweg 6, Leiden, Netherlands., Raboisson P; Janssen Infectious Diseases and Vaccines, Janssen Research & Discovery, Turnhoutseweg 30, Beerse, Belgium., Dhanak D; Discovery Sciences, Janssen Research & Development, Turnhoutseweg 30, Beerse, Belgium.; Discovery Sciences, Janssen Research & Development, 1400 McKean Rd., Spring House, PA, USA., Goudsmit J; Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, Archimedesweg 6, Leiden, Netherlands.; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA., Wilson IA; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA. mvandon@its.jnj.com wilson@scripps.edu.; The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA.
المصدر: Science (New York, N.Y.) [Science] 2019 Mar 08; Vol. 363 (6431).
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 0404511 Publication Model: Print Cited Medium: Internet ISSN: 1095-9203 (Electronic) Linking ISSN: 00368075 NLM ISO Abbreviation: Science
أسماء مطبوعة: Publication: : Washington, DC : American Association for the Advancement of Science
Original Publication: New York, N.Y. : [s.n.] 1880-
مواضيع طبية MeSH: Antibodies, Neutralizing/*chemistry , Biomimetic Materials/*pharmacology , Influenza A Virus, H1N1 Subtype/*drug effects , Influenza, Human/*prevention & control , Piperazines/*pharmacology , Pyridines/*pharmacology , Tetrazoles/*pharmacology , Viral Fusion Protein Inhibitors/*pharmacology , Virus Internalization/*drug effects, Administration, Oral ; Animals ; Biomimetic Materials/administration & dosage ; Biomimetic Materials/pharmacokinetics ; Bronchi/virology ; Cells, Cultured ; Dogs ; Hemagglutinin Glycoproteins, Influenza Virus/genetics ; Hemagglutinin Glycoproteins, Influenza Virus/metabolism ; Humans ; Madin Darby Canine Kidney Cells ; Mice ; Piperazines/administration & dosage ; Piperazines/pharmacokinetics ; Pyridines/administration & dosage ; Pyridines/pharmacokinetics ; Respiratory Mucosa/virology ; Tetrazoles/administration & dosage ; Tetrazoles/pharmacokinetics ; Viral Fusion Protein Inhibitors/administration & dosage ; Viral Fusion Protein Inhibitors/pharmacokinetics
مستخلص: 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.
(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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معلومات مُعتمدة: P41 GM103393 United States GM NIGMS NIH HHS; R56 AI117675 United States AI NIAID NIH HHS; R56 AI127371 United States AI NIAID NIH HHS
المشرفين على المادة: 0 (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)
تواريخ الأحداث: Date Created: 20190309 Date Completed: 20190819 Latest Revision: 20210709
رمز التحديث: 20240829
مُعرف محوري في PubMed: PMC6457909
DOI: 10.1126/science.aar6221
PMID: 30846569
قاعدة البيانات: MEDLINE
الوصف
تدمد:1095-9203
DOI:10.1126/science.aar6221