Abstract
Pandemic influenza virus and SARS-CoV-2 vaiants have posed major global threats to public health. Broad-spectrum antivirals blocking viral entry can be an effective strategy for combating these viruses. Here, we demonstrate a frog-defensin-derived basic peptide (FBP), which broadly inhibits the influenza virus by binding to haemagglutinin so as to block low pH-induced HA-mediated fusion and antagonizes endosomal acidification to inhibit the influenza virus. Moreover, FBP can bind to the SARS-CoV-2 spike to block spike-mediated cell-cell fusion in 293T/ACE2 cells endocytosis. Omicron spike shows a weak cell-cell fusion mediated by TMPRSS2 in Calu3 cells, making the Omicron variant sensitive to endosomal inhibitors. In vivo studies show that FBP broadly inhibits the A(H1N1)pdm09 virus in mice and SARS-CoV-2 (HKU001a and Delta)in hamsters. Notably, FBP shows significant inhibition of Omicron variant replication even though it has a high number of mutations in spike. In conclusion, these results suggest that virus-targeting FBP with a high barrier to drug resistance can be an effective entry-fusion inhibitor against influenza virus and SARS-CoV-2 in vivo.
Keywords:
Antiviral peptide; Delta variant; Omicron variant; SARS-CoV-2; fusion; influenza virus.
MeSH terms
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Animals
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COVID-19 Drug Treatment*
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Influenza A Virus, H1N1 Subtype*
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Mice
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Peptides
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SARS-CoV-2
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Spike Glycoprotein, Coronavirus / genetics
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Spike Glycoprotein, Coronavirus / metabolism
Substances
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Peptides
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Spike Glycoprotein, Coronavirus
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spike protein, SARS-CoV-2
Grants and funding
This study was partly supported by Funding from Health@InnoHK (Centre for Virology, Vaccinology and Therapeutics), Innovation and Technology Commission, The Government of the Hong Kong Special Administrative Region Theme-Based Research Scheme of the Research Grants Council (T11-709/21-N), the National Key Research and Development Programme on Public Security Risk Prevention and Control Emergency Project, Emergency Key Program of Guangzhou Laboratory (EKPG22-01), Funding from the Health and Medical Research Fund, the Food and Health Bureau, The Government of the Hong Kong Special Administrative Region (COVID1903010-Project 13), the National Program on Key Research Project of China [grant numbers 2020YFA0707500 and 2020YFA0707504], the National Key R&D Program of China [grant number 2017YFA0503900], the National Natural Science Foundation of China [grant number 32071270], and the funding from Anhui Provincial Key Laboratory of Molecular Enzymology and Mechanism of Major Diseases and Anhui Provincial Key Laboratory of the Conservation and Exploitation of Biological Resources, and the Consultancy Service for Enhancing Laboratory Surveillance of Emerging Infectious Diseases and Research Capability on Antimicrobial Resistance for Department of Health of the Hong Kong Special Administrative Region Government; and donations of Richard Yu and Carol Yu, Michael Seak-Kan Tong, May Tam Mak Mei Yin, the Shaw Foundation Hong Kong, Providence Foundation Limited (in memory of the late Lui Hac Minh), Lee Wan Keung Charity Foundation Limited, Respiratory Viral Research Foundation Limited, Hui Ming, Hui Hoy and Chow Sin Lan Charity Fund Limited, Chan Yin Chuen Memorial Charitable Foundation, and Marina Man-Wai Lee. The funding sources had no role in the study design, data collection, analysis, interpretation, or report writing.