Preventing Influenza A Virus Infection by Mixed Inhibition of Neuraminidase and Hemagglutinin by Divalent Inhibitors

Abstract

Divalent inhibitors of the neuraminidase enzyme (NA) of the Influenza A virus were synthesized with vastly different spacers. The spacers varied from 14 to 56 atoms and were relatively rigid by way of the building blocks and their connection by CuAAC. As the ligand for these constructs, a Δ 4 -β- d -glucoronide was used, which can be prepared form N -acetyl glucosamine. This ligand showed good NA inhibitory potency but with room for improvement by multivalency enhancement. The synthesized compounds showed modest potency enhancement in NA activity assays but a sizeable potency increase in a 4-day cytopathic effect assay. The demonstration that the compounds can also inhibit hemagglutinin in addition to NA may be the cause of the enhancement.

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.…”

“…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. Hemagglutinin (HA) is becoming an attractive target, which can mediate attachment and membrane fusion in endosomes in the first step of the virus replication cycle. ,− Consequently, several small-molecule inhibitors of HA have been disclosed to effectively combat the IVA. − In 2019, scientists discovered the orally bioavailable JNJ4796, a small molecule mimicking the neutralizing antibody and targeting the stem region of HA, which exhibited nanomolar activity against a broad spectrum of group 1 IAV . Then, Liu and co-workers initiated an optimization campaign of JNJ4796 and identified many derivatives showing good in vitro and in vivo anti-IAV activity .…”