Comprehensive assessment of amino acid substitutions in the trimeric RNA polymerase complex of influenza A virus detected in clinical trials of baloxavir marboxil
| Autor: | Miyako Okane, Steffen Wildum, Keiko Baba, Shinya Omoto, Akira Naito, Takao Shishido, Kae Inoue, Satoshi Hata, Takashi Hashimoto |
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| Rok vydání: | 2020 |
| Předmět: |
Dibenzothiepins
Pulmonary and Respiratory Medicine Pyridones Epidemiology Morpholines Protein subunit RNA polymerase complex 030312 virology medicine.disease_cause Antiviral Agents influenza virus susceptibility Virus 03 medical and health sciences Endonuclease Influenza A Virus H1N1 Subtype Drug Resistance Viral Influenza Human Influenza A virus medicine Humans Polymerase baloxavir Replicative capacity chemistry.chemical_classification 0303 health sciences biology Triazines Influenza A Virus H3N2 Subtype Public Health Environmental and Occupational Health Original Articles DNA-Directed RNA Polymerases antiviral Virology Amino acid Infectious Diseases Amino Acid Substitution chemistry biology.protein Original Article replicative capacity |
| Zdroj: | Influenza and Other Respiratory Viruses |
| ISSN: | 1750-2659 1750-2640 |
| DOI: | 10.1111/irv.12821 |
| Popis: | Background Baloxavir marboxil (BXM) is an approved drug that selectively targets cap‐dependent endonuclease on PA subunit in the RNA polymerase complex of influenza A and B viruses. Amino acid substitutions at position 38 in the PA subunit were identified as a major pathway for reduced susceptibility to baloxavir acid (BXA), the active form of BXM. Additionally, substitutions found at positions E23, A37, and E199 in the PA subunit impact BXA susceptibility by less than 10‐fold. Methods We comprehensively evaluated the impact of novel amino acid substitutions identified in PA, PB1, and PB2 subunits in BXM clinical trials and influenza sequence databases by means of drug susceptibility and replicative capacity. Results PA/I38N in A(H1N1)pdm09 and PA/I38R in A(H3N2) were newly identified as treatment‐emergent substitutions in the CAPSTONE‐2 study. The I38N substitution conferred reduced susceptibility by 24‐fold, whereas replicative capacity of the I38N‐substituted virus was impaired compared with the wild‐type. The I38R‐substituted virus was not viable in cell culture. All other mutations assessed in this extensive study did not significantly affect BXA susceptibility (< 2.4‐fold change). Conclusion These results provide additional information on the impact of amino acid substitutions in the trimeric viral polymerase complex to BXA susceptibility and will further support influenza surveillance. |
| Databáze: | OpenAIRE |
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