Journal article
Effect of pH on small-molecule inhibitor binding to influenza virus hemagglutinin
The Journal of biological chemistry, 111150
01/10/2026
DOI: 10.1016/j.jbc.2026.111150
PMID: 41525845
Abstract
Influenza A viruses (IAVs) impose a tremendous socio-economic burden and the mainstay preventative strategy of using vaccines faces challenges related to annual reformulation and variable efficacy (30-70%). The occurrence of antiviral resistance to the current FDA-approved anti-influenza drugs further highlights the urgent need for novel therapeutics. Our research group previously identified and optimized potent small-molecule inhibitors targeting IAV’s hemagglutinin (HA), a surface glycoprotein crucial for viral entry and membrane fusion. Fusion occurs after the virus is taken up by endocytosis in the late endosomes under acidic conditions (pH ∼4.9-5.5). In this study, we report the biophysical characterization of two small-molecule inhibitors that binds to recombinant H3 and H7 HA proteins (phylogenetic group 2). These two compounds exhibited binding affinities (KD) ranging from ∼0.4 to 18.6 μM and significantly stabilized H7 HA based on thermal shift assay. Remarkably, lowering the pH from 7.2 to 6.2 resulted in up to a ∼267-fold increase in binding strength. Detailed analysis of the compound binding site suggested a potential role of the E97 sidechain in enhancing affinity at lower pH. On the other hand, re-modeling of the compound binding site due to propagated structural changes appears to be the most likely explanation. Collectively, these findings elucidate a pH-dependent mechanism of action for HA-targeting antivirals and underscore the importance of evaluating protein-ligand interactions under physiologically relevant conditions. This consideration is particularly important for viral proteins such as IAV HA that undergo pH-triggered conformational changes during the endosome-dependent viral entry.
Details
- Title: Subtitle
- Effect of pH on small-molecule inhibitor binding to influenza virus hemagglutinin
- Creators
- Varada Anirudhan - University of Illinois ChicagoIrina Gaisina - University of Illinois ChicagoAmir Shimon - University of Illinois ChicagoHyun Lee - University of Illinois ChicagoSaad Alqarni - University of Ha'ilBalaji Manicassamy - University of IowaTerry W. Moore - University of Illinois ChicagoKai Xu - The Ohio State UniversityMichael Caffrey - University of Illinois ChicagoLijun Rong - University of Illinois Chicago
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, 111150
- DOI
- 10.1016/j.jbc.2026.111150
- PMID
- 41525845
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- Elsevier Inc
- Language
- English
- Electronic publication date
- 01/10/2026
- Academic Unit
- Microbiology and Immunology
- Record Identifier
- 9985121597502771
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