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

Irina N. Gaisina; Norton P. Peet; Han Cheng; Ping Li; Ruikun Du; Qinghua Cui; Kevin Furlong; Balaji Manicassamy; Michael Caffrey; Gregory R. J. Thatcher; Lijun Rong

doi:10.1021/acs.jmedchem.9b01900

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

Journal article

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

Irina N. Gaisina, Norton P. Peet, Han Cheng, Ping Li, Ruikun Du, Qinghua Cui, Kevin Furlong, Balaji Manicassamy, Michael Caffrey, Gregory R. J. Thatcher, …

Journal of medicinal chemistry, Vol.63(6), pp.3120-3130

03/26/2020

DOI: 10.1021/acs.jmedchem.9b01900

PMCID: PMC8827112

PMID: 32069052

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https://www.ncbi.nlm.nih.gov/pmc/articles/8827112View

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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.

Chemistry, Medicinal

Life Sciences & Biomedicine

Pharmacology & Pharmacy

Science & Technology

Details

Title: Subtitle: Optimization of 4-Aminopiperidines as Inhibitors of Influenza A Viral Entry That Are Synergistic with Oseltamivir
Creators: Irina N. Gaisina - University of Illinois Chicago
Norton P. Peet - Chicago BioSolutions, Inc., 2242 West Harrison Street, Chicago, Illinois 60612, United States.
Han Cheng - University of Illinois Chicago
Ping Li - Shandong University of Traditional Chinese Medicine
Ruikun Du - Shandong University of Traditional Chinese Medicine
Qinghua Cui - Shandong University of Traditional Chinese Medicine
Kevin Furlong - University of Chicago
Balaji Manicassamy - University of Iowa
Michael Caffrey - University of Illinois Chicago
Gregory R. J. Thatcher - University of Illinois Chicago
Lijun Rong - University of Illinois Chicago
Resource Type: Journal article
Publication Details: Journal of medicinal chemistry, Vol.63(6), pp.3120-3130
DOI: 10.1021/acs.jmedchem.9b01900
PMID: 32069052
PMCID: PMC8827112
NLM abbreviation: J Med Chem
ISSN: 0022-2623
eISSN: 1520-4804
Publisher: Amer Chemical Soc
Number of pages: 11
Grant note: AI127031 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
Language: English
Date published: 03/26/2020
Academic Unit: Microbiology and Immunology
Record Identifier: 9984297439302771

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