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Optimization of 4-Aminopiperidines as Inhibitors of Influenza A Viral Entry That Are Synergistic with Oseltamivir

  • Irina N. Gaisina*
    Irina N. Gaisina
    UICentre (Drug Discovery@UIC) and Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United States
    Chicago BioSolutions, Inc., 2242 West Harrison Street, Chicago, Illinois 60612, United States
    *E-mail: [email protected]. Tel: +1-312-413-0284. Fax: +1-312-996-7107 (I.N.G.).
  • Norton P. Peet*
    Norton P. Peet
    Chicago BioSolutions, Inc., 2242 West Harrison Street, Chicago, Illinois 60612, United States
    *E-mail: [email protected]. Tel: +1-978-804-8099 (N.P.P.).
  • Han Cheng
    Han Cheng
    Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, 909 South Wolcott Avenue, Chicago, Illinois 60612, United States
    More by Han Cheng
  • Ping Li
    Ping Li
    College of Pharmacy, Shandong University of Traditional Chinese Medicine, 16369 Jinshi Road, Jinan, Shandong 250355, China
    More by Ping Li
  • Ruikun Du
    Ruikun Du
    College of Pharmacy, Shandong University of Traditional Chinese Medicine, 16369 Jinshi Road, Jinan, Shandong 250355, China
    More by Ruikun Du
  • Qinghua Cui
    Qinghua Cui
    College of Pharmacy, Shandong University of Traditional Chinese Medicine, 16369 Jinshi Road, Jinan, Shandong 250355, China
    More by Qinghua Cui
  • Kevin Furlong
    Kevin Furlong
    Department of Microbiology, University of Chicago, 920 East 58th Street, Chicago, Illinois 60637, United States
  • Balaji Manicassamy
    Balaji Manicassamy
    Department of Microbiology and Immunology, University of Iowa, 51 Newton Road, Iowa City, Iowa 52242, United States
    Department of Microbiology, University of Chicago, 920 East 58th Street, Chicago, Illinois 60637, United States
  • Michael Caffrey
    Michael Caffrey
    Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, 900 South Ashland Avenue, Chicago, Illinois 60607, United States
  • Gregory R. J. Thatcher
    Gregory R. J. Thatcher
    UICentre (Drug Discovery@UIC) and Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United States
  • , and 
  • Lijun Rong*
    Lijun Rong
    Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, 909 South Wolcott Avenue, Chicago, Illinois 60612, United States
    *E-mail: [email protected]. Tel/Fax: +1-312-355-0203 (L.R.).
    More by Lijun Rong
Cite this: J. Med. Chem. 2020, 63, 6, 3120–3130
Publication Date (Web):February 18, 2020
https://doi.org/10.1021/acs.jmedchem.9b01900
Copyright © 2020 American Chemical Society

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    Abstract

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    Vaccination is the most prevalent prophylactic means for controlling seasonal influenza infections. However, an effective vaccine usually takes at least 6 months to develop for the circulating strains. Therefore, new therapeutic options are needed for the acute treatment of influenza infections to control this virus and prevent epidemics/pandemics from developing. We have discovered fast-acting, orally bioavailable acylated 4-aminopiperidines with an effective mechanism of action targeting viral hemagglutinin (HA). Our data show that these compounds are potent entry inhibitors of influenza A viruses. We present docking studies that suggest an HA binding site for these inhibitors on H5N1. Compound 16 displayed a significant decrease of viral titer when evaluated in the infectious assays with influenza virus H1N1 (A/Puerto Rico/8/1934) or H5N1 (A/Vietnam/1203/2004) strains and the oseltamivir-resistant strain with the most common H274Y mutation. In addition, compound 16 showed significant synergistic activity with oseltamivir in vitro.

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.9b01900.

    • Experimental procedures describing general experimental information and biological assays; virus titer reduction assay with influenza A virus (H1N1) H274Y (Figure S1); characterization of the oseltamivir-resistant strain of influenza A virus (H1N1) (Figure S2); oseltamivir carboxylate and compound 16 display synergistic combination index values for anti-influenza activity (Figure S3); infectious virus replication inhibition assay (plaque assay) (Figure S4) (PDF)

    • Molecular formula strings (CSV)

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