Approaches for discovery of small-molecular antivirals targeting to influenza A virus PB2 subunit

Phosphorylation of PB2 at serine 181 restricts viral replication and virulence of the highly pathogenic H5N1 avian influenza virus in mice

“…Of note, we failed to rescue the rPB2-K187R recombinant virus, suggesting that deacetylation of K187 may be detrimental to the formation of virions. Considering that the cap-binding PB2 protein has key functions in viral transcription and replication ( Stevaert and Naesens, 2016 ; Lo et al., 2018 ; Chen et al., 2022 ), loss of acetylation of PB2 K187 may impede important steps of the IAV life cycle and finally result in the failure of virus recovery. It is worth noting that a recent study identified that PB2 K187 is ubiquitinated ( Günl et al., 2023 ).…”

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

“…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 . Although oseltamivir as an NAI can be administrated orally and exhibits broad-spectrum antiviral potencies, the emergence of resistance undermines its efficacy. ,− Therefore, it is highly urgent and desirable to develop more effective, nontoxic, structurally novel antivirals with alternative targets.…”

Cap snatch prevention: a novel approach to tackle influenza viruses

“…Of note, the PB2 subunit of the IAV polymerase has previously been recognized as a promising drug target. 5 However, no inhibitors of the cellular MTr1 enzyme have been reported.…”