The convergent evolution of influenza A virus: Implications, therapeutic strategies and what we need to know

Low, Zheng Yao; Wong, Ka Heng; Wen Yip, Ashley Jia; Choo, Wee Sim

doi:10.1016/j.crmicr.2023.100202

Cited by 4 publications

(2 citation statements)

References 220 publications

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“…Influenza A virus (IAV) is a highly contagious respiratory pathogen and causes about hundreds of thousands of deaths in worldwide seasonal epidemics every year. Not only did IAV cause high morbidity and mortality, but also it brings serious threat to the global public health, especially the widespread subtype H1N1, which caused quite serious pandemics in both 1918 and 2009, and successive epidemics until now. − Seasonal influenza vaccination still remains the prevalent prophylactic means for controlling IAV infections. However, its efficacy is remarkably less effective for individuals with compromised immunity and its availability is highly dependent on the accurate forecast of the circulating strains. − Besides, small molecules offer an important therapeutic option to prevent and treat influenza. ,− Until now, Food and Drug Administration has approved three major types of antivirals with different mechanisms of action (MOAs), including M2 ion-channel blockers, neuraminidase inhibitors (NAIs), and RNA-dependent RNA polymerase (RdRp) inhibitors (Figure A). − It should be noted that the representative M2 ion-channel blockers (amantadine and rimantadine) are not recommended anymore due to the ineffectiveness against circulating influenza strains .…”

Section: Introductionmentioning

confidence: 99%

Modular Biomimetic Strategy Enables Discovery and SAR Exploration of Oxime Macrocycles as Influenza A Virus (H1N1) Inhibitors

Xu,

Gong,

Zhang

et al. 2024

J. Med. Chem.

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Although vaccination remains the prevalent prophylactic means for controlling Influenza A virus (IAV) infections, novel structural antivirus small-molecule drugs with new mechanisms of action for treating IAV are highly desirable. Herein, we describe a modular biomimetic strategy to expeditiously achieve a new class of macrocycles featuring oxime, which might target the hemagglutinin (HA)-mediated IAV entry into the host cells. SAR analysis revealed that the size and linker of the macrocycles play an important role in improving potency. Particularly, as a 14-membered macrocyclic oxime, 37 exhibited potent inhibitory activity against IAV H1N1 with an EC50 value of 23 nM and low cytotoxicity, which alleviated cytopathic effects and protected cell survival obviously after H1N1 infection. Furthermore, 37 showed significant synergistic activity with neuraminidase inhibitor oseltamivir in vitro.

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Section: Introductionmentioning

confidence: 99%

Modular Biomimetic Strategy Enables Discovery and SAR Exploration of Oxime Macrocycles as Influenza A Virus (H1N1) Inhibitors

Xu,

Gong,

Zhang

et al. 2024

J. Med. Chem.

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“…This requires additional doses to maintain protection against the infection [ 12 ]. Current drug development against influenza is focused on small molecules and neutralizing antibodies, which require high doses (1–2 g) or frequent re-dosing (multiple times per day for multiple days) to obtain functional outcomes, and they are often plagued by strain limitations (influenza A/B) and antigenic changes [ 13 ]. In addition, oseltamivir, favipiravir, pimodivir and baloxavir marboxil have been shown to induce development of resistance over time, with significant (>20 fold) decreases in efficacy against multiple influenza strains [ 14 – 16 ].…”

Section: Introductionmentioning

confidence: 99%

mRNA-encoded Cas13 treatment of Influenza via site-specific degradation of genomic RNA

Chaves,

Orr-Burks,

Vanover

et al. 2024

PLoS Pathog

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The CRISPR-Cas13 system has been proposed as an alternative treatment of viral infections. However, for this approach to be adopted as an antiviral, it must be optimized until levels of efficacy rival or exceed the performance of conventional approaches. To take steps toward this goal, we evaluated the influenza viral RNA degradation patterns resulting from the binding and enzymatic activity of mRNA-encoded LbuCas13a and two crRNAs from a prior study, targeting PB2 genomic and messenger RNA. We found that the genome targeting guide has the potential for significantly higher potency than originally detected, because degradation of the genomic RNA is not uniform across the PB2 segment, but it is augmented in proximity to the Cas13 binding site. The PB2 genome targeting guide exhibited high levels (>1 log) of RNA degradation when delivered 24 hours post-infection in vitro and maintained that level of degradation over time, with increasing multiplicity of infection (MOI), and across modern influenza H1N1 and H3N2 strains. Chemical modifications to guides with potent LbuCas13a function, resulted in nebulizer delivered efficacy (>1–2 log reduction in viral titer) in a hamster model of influenza (Influenza A/H1N1/California/04/09) infection given prophylactically or as a treatment (post-infection). Maximum efficacy was achieved with two doses, when administered both pre- and post-infection. This work provides evidence that mRNA-encoded Cas13a can effectively mitigate Influenza A infections opening the door to the development of a programmable approach to treating multiple respiratory infections.

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Sequence and Phylogenetic Analysis of Influenza Virus (H1N1pdm2009) Circulating in Riyadh, Saudi Arabia

Al Shammari

2024

J. Pure Appl. Microbiol.

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Influenza A virus (IAV) is the principal cause of seasonal flu and is often reported among pilgrims in Saudi Arabia (SA) due to their mass gatherings. The epidemiological, phylogenetic, and molecular details of A/H1N1pdm2009 in 200 clinical samples collected from hospitalized children in Riyadh during two epidemic seasons (2020/21 and 2021/22) are reported in this study. A total of 21 (10.50%) samples were positive for IAV, as determined using PCR. Fifteen isolates (71.42%) were identified as H1N1pdm2009: eight (53.33%) samples were from males, seven (46.67%) from females. The prevalence of H1N1pdm2009 isolates was significantly (p < 0.05) higher among the age group 15-64 years than the other age groups. A comparison of hemagglutinin (HA) and neuraminidase (NA) amino acid sequences between SA H1N1pdm and certain vaccine strains revealed 19 mutations relative to reference strain A/California/07/2009. Among them, eight (0.47%) were in HA, and eight (0.56%) were in NA sequences that differed from vaccine strains. All isolates of the 2020–2022 seasons exhibited N- and O-glycosylation sites comparable to vaccine strains. Phylogenetically their HA and NA genes are divided into different clades. Most of the studied isolates (five) belonged to clade 5a.1 of HA. These data identify the genetic makeup of circulating influenza virus subtypes.

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The convergent evolution of influenza A virus: Implications, therapeutic strategies and what we need to know

Cited by 4 publications

References 220 publications

Modular Biomimetic Strategy Enables Discovery and SAR Exploration of Oxime Macrocycles as Influenza A Virus (H1N1) Inhibitors

Modular Biomimetic Strategy Enables Discovery and SAR Exploration of Oxime Macrocycles as Influenza A Virus (H1N1) Inhibitors

mRNA-encoded Cas13 treatment of Influenza via site-specific degradation of genomic RNA

Sequence and Phylogenetic Analysis of Influenza Virus (H1N1pdm2009) Circulating in Riyadh, Saudi Arabia

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