Identification of epidermal growth factor receptor-tyrosine kinase inhibitor targeting the VP1 pocket of human rhinovirus
Screening a library of 1,200 preselected kinase inhibitors for anti-human rhinovirus 2 (HRV-2) activity in HeLa cells identified a class of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) as effective virus blockers. These were based on the 4-anilinoquinazoline-7-oxypiperidine scaffold, with the most potent representative AZ5385 inhibiting the virus with EC50 of 0.35 µM. Several structurally related analogs confirmed activity in the low µM range, while interestingly, other TKIs targeting EGFR lacked anti-HRV-2 activity. To further probe this lack of association between antiviral activity and EGFR inhibition, we stained infected cells with antibodies specific for activated EGFR (Y1068) and did not observe a dependency on EGFR-TK activity. Instead, consecutive passages of HRV-2 in HeLa cells in the presence of a compound and subsequent nucleotide sequence analysis of resistant viral variants identified the S181T and T210A alterations in the major capsid VP1 protein, with both residues located in the vicinity of a known hydrophobic pocket on the viral capsid. Further characterization of the antiviral effects of AZ5385 showed a modest virus-inactivating (virucidal) activity, while anti-HRV-2 activity was still evident when the inhibitor was added as late as 10 h post infection. The RNA copy/infectivity ratio of HRV-2 propagated in AZ5385 presence was substantially higher than that of control HRV indicating that the compound preferentially targeted HRV progeny virions during their maturation in infected cells. Besides HRV, the compound showed anti-respiratory syncytial virus activity, which warrants its further studies as a candidate compound against viral respiratory infections.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:68 |
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| Enthalten in: |
Antimicrobial agents and chemotherapy - 68(2024), 3 vom: 06. März, Seite e0106423 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Miah, Masum [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 07.03.2024 Date Revised 08.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1128/aac.01064-23 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM368392880 |
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| 245 | 1 | 0 | |a Identification of epidermal growth factor receptor-tyrosine kinase inhibitor targeting the VP1 pocket of human rhinovirus |
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| 520 | |a Screening a library of 1,200 preselected kinase inhibitors for anti-human rhinovirus 2 (HRV-2) activity in HeLa cells identified a class of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) as effective virus blockers. These were based on the 4-anilinoquinazoline-7-oxypiperidine scaffold, with the most potent representative AZ5385 inhibiting the virus with EC50 of 0.35 µM. Several structurally related analogs confirmed activity in the low µM range, while interestingly, other TKIs targeting EGFR lacked anti-HRV-2 activity. To further probe this lack of association between antiviral activity and EGFR inhibition, we stained infected cells with antibodies specific for activated EGFR (Y1068) and did not observe a dependency on EGFR-TK activity. Instead, consecutive passages of HRV-2 in HeLa cells in the presence of a compound and subsequent nucleotide sequence analysis of resistant viral variants identified the S181T and T210A alterations in the major capsid VP1 protein, with both residues located in the vicinity of a known hydrophobic pocket on the viral capsid. Further characterization of the antiviral effects of AZ5385 showed a modest virus-inactivating (virucidal) activity, while anti-HRV-2 activity was still evident when the inhibitor was added as late as 10 h post infection. The RNA copy/infectivity ratio of HRV-2 propagated in AZ5385 presence was substantially higher than that of control HRV indicating that the compound preferentially targeted HRV progeny virions during their maturation in infected cells. Besides HRV, the compound showed anti-respiratory syncytial virus activity, which warrants its further studies as a candidate compound against viral respiratory infections | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a epidermal growth factor receptor | |
| 650 | 4 | |a escape mutant | |
| 650 | 4 | |a human rhinovirus | |
| 650 | 4 | |a hydrophobic pocket | |
| 650 | 4 | |a kinase inhibitor | |
| 650 | 7 | |a Tyrosine Kinase Inhibitors |2 NLM | |
| 650 | 7 | |a Capsid Proteins |2 NLM | |
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| 700 | 1 | |a Davis, Andrew M |e verfasserin |4 aut | |
| 700 | 1 | |a Hannoun, Charles |e verfasserin |4 aut | |
| 700 | 1 | |a Said, Joanna S |e verfasserin |4 aut | |
| 700 | 1 | |a Fitzek, Martina |e verfasserin |4 aut | |
| 700 | 1 | |a Preston, Marian |e verfasserin |4 aut | |
| 700 | 1 | |a Smith, Dave |e verfasserin |4 aut | |
| 700 | 1 | |a Uwamariya, Colores |e verfasserin |4 aut | |
| 700 | 1 | |a Kärmander, Ambjörn |e verfasserin |4 aut | |
| 700 | 1 | |a Lundbäck, Thomas |e verfasserin |4 aut | |
| 700 | 1 | |a Bergström, Tomas |e verfasserin |4 aut | |
| 700 | 1 | |a Trybala, Edward |e verfasserin |4 aut | |
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