Identification of entry inhibitors with 4-aminopiperidine scaffold targeting group 1 influenza A virus

Amira F.A. Hussein; Han Cheng; Smanla Tundup; Aleksandar Antanasijevic; Elizabeth Varhegyi; Jasmine Perez; Eiman M. AbdulRahman; Mervat G Elenany; Soheir Helal; Michael Caffrey; Norton Peet; Balaji Manicassamy; Lijun Rong

doi:10.1016/j.antiviral.2020.104782

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Identification of entry inhibitors with 4-aminopiperidine scaffold targeting group 1 influenza A virus

Journal article

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Identification of entry inhibitors with 4-aminopiperidine scaffold targeting group 1 influenza A virus

Amira F.A. Hussein, Han Cheng, Smanla Tundup, Aleksandar Antanasijevic, Elizabeth Varhegyi, Jasmine Perez, Eiman M. AbdulRahman, Mervat G Elenany, Soheir Helal, Michael Caffrey, …

Antiviral research, Vol.177, pp.104782-104782

03/25/2020

DOI: 10.1016/j.antiviral.2020.104782

PMCID: PMC7243365

PMID: 32222293

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https://www.ncbi.nlm.nih.gov/pmc/articles/7243365View

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Abstract

Influenza A viruses (IAVs) cause seasonal flu and occasionally pandemics. The current therapeutics against IAVs target two viral proteins - neuraminidase (NA) and M2 ion-channel protein. However, M2 ion channel inhibitors (amantadine and rimantadine) are no longer recommended by CDC for use due to the emergence of high level of antiviral resistance among the circulating influenza viruses, and resistant strains to NA inhibitors (oseltamivir and zanamivir) have also been reported. Therefore, development of novel anti-influenza therapies is urgently needed. As one of the viral surface glycoproteins, hemagglutinin (HA) mediates critical virus entry steps including virus binding to host cells and virus-host membrane fusion, which makes it a potential target for anti-influenza drug development. In this study, we report the identification of compound CBS1116 with a 4-aminopiperidine scaffold from a chemical library screen as an entry inhibitor specifically targeting two group 1 influenza A viruses, A/Puerto Rico/8/34 (H1N1) and recombinant low pathogenic avian H5N1 virus (A/Vietnam/1203/04, VN04 Low ). Mechanism of action study shows that CBS1116 interferes with the HA-mediated fusion process. Further structure activity relationship study generated a more potent compound CBS1117 which has a 50% inhibitory concentration of 70 nM and a selectivity index of ~4000 against A/Puerto Rico/8/34 (H1N1) infection in human lung epithelial cell line (A549).

fusion inhibitor

hemagglutinin

Influenza A viruses

structure activity relationship

virus entry

Details

Title: Subtitle: Identification of entry inhibitors with 4-aminopiperidine scaffold targeting group 1 influenza A virus
Creators: Amira F.A. Hussein - University of Illinois Chicago
Han Cheng - University of Illinois Chicago
Smanla Tundup - Argonne National Laboratory
Aleksandar Antanasijevic - University of Illinois Chicago
Elizabeth Varhegyi - University of Illinois Chicago
Jasmine Perez - University of Chicago
Eiman M. AbdulRahman - Cairo University
Mervat G Elenany - University of Illinois Chicago
Soheir Helal - Cairo University
Michael Caffrey - University of Illinois Chicago
Norton Peet - University of Illinois Chicago
Balaji Manicassamy - Argonne National Laboratory
Lijun Rong - University of Illinois Chicago
Resource Type: Journal article
Publication Details: Antiviral research, Vol.177, pp.104782-104782
DOI: 10.1016/j.antiviral.2020.104782
PMID: 32222293
PMCID: PMC7243365
NLM abbreviation: Antiviral Res
ISSN: 0166-3542
eISSN: 1872-9096
Grant note: DOI: 10.13039/100000002, name: National Institutes of Health, award: AI127031
Language: English
Date published: 03/25/2020
Academic Unit: Microbiology and Immunology
Record Identifier: 9984297320002771

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