Journal article
Structure of avian influenza hemagglutinin in complex with a small molecule entry inhibitor
Life science alliance, Vol.3(8), p.e202000724
08/01/2020
DOI: 10.26508/lsa.202000724
PMCID: PMC7335401
PMID: 32611549
Abstract
HA plays a critical role in influenza infection and, thus HA is a potential target for antivirals. Recently, our laboratories have described a novel fusion inhibitor, termed CBS1117, with EC50 similar to 3 mu M against group 1 HA. In this work, we characterize the binding properties of CBS1117 to avian H5 HA by x-ray crystallography, NMR, and mutagenesis. The x-ray structure of the complex shows that the compound binds near the HA fusion peptide, a region that plays a critical role in HA-mediated fusion. NMR studies demonstrate binding of CBS1117 to H5 HA in solution and show extensive hydrophobic contacts between the compound and HA surface. Mutagenesis studies further support the location of the compound binding site proximal to the HA fusion peptide and identify additional amino acids that are important to compound binding. Together, this work gives new insights into the CBS1117 mechanism of action and can be exploited to further optimize this compound and better understand the group specific activity of small-molecule inhibitors of HA-mediated entry.
Details
- Title: Subtitle
- Structure of avian influenza hemagglutinin in complex with a small molecule entry inhibitor
- Creators
- Aleksandar Antanasijevic - University of Illinois ChicagoMatthew A. Durst - University of Illinois ChicagoHan Cheng - University of Illinois ChicagoIrina N. Gaisina - Chicago BioSolutions, Inc., Chicago, IL, USA.Jasmine T. Perez - University of IowaBalaji Manicassamy - University of IowaLijun Rong - University of Illinois ChicagoArnon Lavie - University of Illinois ChicagoMichael Caffrey - University of Illinois Chicago
- Resource Type
- Journal article
- Publication Details
- Life science alliance, Vol.3(8), p.e202000724
- DOI
- 10.26508/lsa.202000724
- PMID
- 32611549
- PMCID
- PMC7335401
- NLM abbreviation
- Life Sci Alliance
- ISSN
- 2575-1077
- eISSN
- 2575-1077
- Publisher
- Life Science Alliance Llc
- Number of pages
- 8
- Grant note
- Searle Funds at the Chicago Community Trust Chicago Biomedical Consortium R01AI123359; R01AI127775 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R41AI127031; R41AI145727 / National Institutes of Health (NIH); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 08/01/2020
- Academic Unit
- Microbiology and Immunology
- Record Identifier
- 9984297424602771
Metrics
15 Record Views