Influenza A virus polymerase acidic protein E23R substitution is a marker of reduced susceptibility to baloxavir

Jc, Jones; Rovito, Samuel W; Penaflor, Melissa K; Webby, Richard J.; Govorkova, Elena A.

doi:10.1016/j.antiviral.2022.105369

Cited by 5 publications

(3 citation statements)

References 14 publications

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“…A previous study showed that PA I38T/M emerged as the predominant baloxavir-resistant site, affecting up to 9.5% of cases ( Yang, 2019 ). Moreover, substitutions at other PA residues (E23G/K, A37T, and E199G) were observed after baloxavir treatment ( Ince et al, 2020 ; Jones et al, 2022a , b ; Takashita et al, 2023 ). Given the high replication rate and lack of proofreading of the viruses under the selective pressure of antiviral treatment, the emergence of resistance to baloxavir was also considered in the current study.…”

Section: Discussionmentioning

confidence: 98%

Prospective observational study of baloxavir marboxil in adults and adolescents with uncomplicated influenza from China

Liao,

Xia,

Jiang

et al. 2023

Front. Microbiol.

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IntroductionThere are limited data on the efficacy of baloxavir marboxil (baloxavir) versus oseltamivir in Chinese patients with influenza A.MethodsThis study is an observational real-world investigation encompassing 246 patients (baloxavir, n = 147; oseltamivir, n = 99) confirmed positive for influenza A. The choice between baloxavir and oseltamivir antiviral treatments was determined collaboratively by the clinician and the patient. A thorough comparative analysis was undertaken between the two groups, examining parameters such as the duration of fever and symptoms, viral load dynamics, lymphocyte changes, and enhancements in health-related quality of life (QoL).ResultsNo significant differences were observed in demographic data between the two groups. The duration of fever was significantly shorter in the baloxavir group (P < 0.001). However, the duration of symptoms was not significant different (P = 0.167). Multivariable Cox analysis showed the independent factors affecting duration of fever were baloxavir treatment (HR = 2.033, P < 0.001), fever on day 1 (HR = 0.741, P = 0.010) and CRP level (HR = 1.009, P = 0.039). Moreover, sex (HR= 0.660, P = 0.019) and monocyte count (HR = 1.355, P = 0.018) were independent factors affecting the duration of symptoms. No significant difference in change of health-related quality of life (P > 0.05), positive rate of viral antigen on day 3 (P = 0.477) between the two groups. Remarkably, a mutation was observed in one case on the third-day after baloxavir treatment compared with first-day, from cysteine to serine at position 384 of the PA subunit.ConclusionIn the clinical setting, baloxavir demonstrated comparable clinical benefits to oseltamivir, establishing its efficacy as an effective antiviral therapy for Chinese patients with influenza.

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Section: Discussionmentioning

confidence: 98%

Prospective observational study of baloxavir marboxil in adults and adolescents with uncomplicated influenza from China

Liao,

Xia,

Jiang

et al. 2023

Front. Microbiol.

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“…In the recent years, there has been increased interest in harnessing targeted protein degradation (TPD) technology in the development of antiviral therapies by inducing the degradation of either viral or host-related protein targets, but the off-target side effects and toxicity greatly limit its use [54][55][56][57]. In this study, we found the N-terminus of host protein BAG6 contains a ubiquitin-like domain (UBL, 17-92aa), which was previously reported to recruit E3 ligase RNF126 and ubiquitinates BAG6-associated clients [40], and a PB2-binding domain (124-186aa), which was proved to interact with viral polymerase subunit PB2 protein during IAV infection.…”

Section: Plos Pathogensmentioning

confidence: 99%

BAG6 inhibits influenza A virus replication by inducing viral polymerase subunit PB2 degradation and perturbing RdRp complex assembly

Zhou,

Li,

Zhang

et al. 2024

PLoS Pathog

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The interaction between influenza A virus (IAV) and host proteins is an important process that greatly influences viral replication and pathogenicity. PB2 protein is a subunit of viral ribonucleoprotein (vRNP) complex playing distinct roles in viral transcription and replication. BAG6 (BCL2-associated athanogene 6) as a multifunctional host protein participates in physiological and pathological processes. Here, we identify BAG6 as a new restriction factor for IAV replication through targeting PB2. For both avian and human influenza viruses, overexpression of BAG6 reduced viral protein expression and virus titers, whereas deletion of BAG6 significantly enhanced virus replication. Moreover, BAG6-knockdown mice developed more severe clinical symptoms and higher viral loads upon IAV infection. Mechanistically, BAG6 restricted IAV transcription and replication by inhibiting the activity of viral RNA-dependent RNA polymerase (RdRp). The co-Immunoprecipitation assays showed BAG6 specifically interacted with the N-terminus of PB2 and competed with PB1 for RdRp complex assembly. The ubiquitination assay indicated that BAG6 promoted PB2 ubiquitination at K189 residue and targeted PB2 for K48-linked ubiquitination degradation. The antiviral effect of BAG6 necessitated its N-terminal region containing a ubiquitin-like (UBL) domain (17-92aa) and a PB2-binding domain (124-186aa), which are synergistically responsible for viral polymerase subunit PB2 degradation and perturbing RdRp complex assembly. These findings unravel a novel antiviral mechanism via the interaction of viral PB2 and host protein BAG6 during avian or human influenza virus infection and highlight a potential application of BAG6 for antiviral drug development.

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“…Baloxavir marboxil ( 7 ) is currently the only PA inhibitor in the market. Unfortunately, the PA I38T substitution is observed in circulating viruses and confers resistance to baloxavir marboxil, while E23R has a synergistic effect and increases baloxavir EC 50 values by > 10-fold 28 . In addition, cross-resistance has been observed in a number of drugs.…”

Section: Introductionmentioning

confidence: 99%

Emerging drug design strategies in anti-influenza drug discovery

Liu

Dong

et al. 2023

Acta Pharmaceutica Sinica B

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Influenza A virus polymerase acidic protein E23R substitution is a marker of reduced susceptibility to baloxavir

Cited by 5 publications

References 14 publications

Prospective observational study of baloxavir marboxil in adults and adolescents with uncomplicated influenza from China

Prospective observational study of baloxavir marboxil in adults and adolescents with uncomplicated influenza from China

BAG6 inhibits influenza A virus replication by inducing viral polymerase subunit PB2 degradation and perturbing RdRp complex assembly

Emerging drug design strategies in anti-influenza drug discovery

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