2. Academic Validation
  3. Optimization of 4-Aminopiperidines as Inhibitors of Influenza A Viral Entry That Are Synergistic with Oseltamivir

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

  • J Med Chem. 2020 Mar 26;63(6):3120-3130. doi: 10.1021/acs.jmedchem.9b01900.
Irina N Gaisina 1 2,  Norton P Peet 2,  Han Cheng 3,  Ping Li 4,  Ruikun Du 4,  Qinghua Cui 4,  Kevin Furlong 5,  Balaji Manicassamy 5 6,  Michael Caffrey 7,  Gregory R J Thatcher 1,  Lijun Rong 3
Affiliations

Affiliations

  • 1 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.
  • 2 Chicago BioSolutions, Inc., 2242 West Harrison Street, Chicago, Illinois 60612, United States.
  • 3 Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, 909 South Wolcott Avenue, Chicago, Illinois 60612, United States.
  • 4 College of Pharmacy, Shandong University of Traditional Chinese Medicine, 16369 Jinshi Road, Jinan, Shandong 250355, China.
  • 5 Department of Microbiology, University of Chicago, 920 East 58th Street, Chicago, Illinois 60637, United States.
  • 6 Department of Microbiology and Immunology, University of Iowa, 51 Newton Road, Iowa City, Iowa 52242, United States.
  • 7 Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, 900 South Ashland Avenue, Chicago, Illinois 60607, United States.
PMID: 32069052 DOI: 10.1021/acs.jmedchem.9b01900
Abstract

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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