Potential Role of Superoxide Dismutase 3 (SOD3) in Resistance to Influenza A Virus Infection.

Influenza A virus infection induces the production of excessive reactive oxygen species (ROS). Overproduction of ROS can overwhelm the antioxidant defense system, leading to increasing intensive oxidative stress. However, antioxidant defense against oxidative damage induced by influenza A virus infection, and in particular the significance of the SOD3 response in the pathogenesis of influenza virus infection, has not been well characterized. Here, we investigated the potential role of SOD3 in resistance to influenza A virus infection. In this study, SOD3, as an important antioxidant enzyme, was shown to be highly elevated in A549 cells following influenza A virus infection. Furthermore, inhibition of SOD3 impacted viral replication and virulence. We found that SOD3 disrupts IAV replication by impairing the synthesis of vRNA, whereas it did not affect viral ribonucleoprotein nuclear export. In addition, overexpression of SOD3 greatly reduced the levels of ROS caused by influenza A virus infection, regulated the inflammatory response to virus infection by inhibiting the phosphorylation of p65 of the NF-κB signaling pathway, and inhibited virus-induced apoptosis to a certain extent. Taken together, these findings indicate that SOD3 is actively involved in influenza A virus replication. Pharmacological modulation or targeting of SOD3 may pave the way for a novel therapeutic approach to combating influenza A virus infection.

Methyl brevifolincarboxylate, a novel influenza virus PB2 inhibitor from Canarium Album (Lour.) Raeusch.

Methyl brevifolincarboxylate (MBC) was isolated from ethyl acetate extract of Canarium album (Lour.) Raeusch. The structure was identified, and the effect on influenza A virus infection was evaluated. MBC exhibited inhibitory activity against influenza virus A/Puerto Rico/8/34 (H1N1) and A/Aichi/2/68 (H3N2) with IC50 values of 27.16 ± 1.39 µM and 33.41 ± 2.34 µM. Mechanism studies indicated that MBC inhibited the replication of influenza A virus by targeting PB2 cap-binding domain. Our results demonstrated MBC was a potent PB2 cap-binding inhibitor and represented as a new type of promising lead compound for the development of anti-influenza virus drugs from natural products.

Spirostaphylotrichin X from a Marine-Derived Fungus as an Anti-influenza Agent Targeting RNA Polymerase PB2.

A new spirocyclic γ-lactam, named spirostaphylotrichin X (1), and three related known spirostaphylotrichins (2-4) were isolated from the marine-derived fungus Cochliobolus lunatus SCSIO41401. Their structures were determined by spectroscopic analyses. Spirostaphylotrichin X (1) displayed obvious inhibitory activities against multiple influenza virus strains, with IC50 values from 1.2 to 5.5 µM. Investigation of the mechanism showed that 1 inhibited viral polymerase activity and interfered with the production of progeny viral RNA. Homogeneous time-resolved fluorescence, surface plasmon resonance assays, and a molecular docking study revealed that 1 could inhibit polymerase PB2 protein activity by binding to the highly conserved region of the cap-binding domain of PB2. These results suggest that 1 inhibits the replication of influenza A virus by interfering with the activity of PB2 protein and that 1 represents a new type of potential lead compound for the development of anti-influenza therapeutics.

A Small-Molecule Compound Has Anti-influenza A Virus Activity by Acting as a ''PB2 Inhibitor".

With regular influenza epidemics and the prevalence of drug-resistant influenza virus strains, it is extremely crucial to develop effective and low-toxicity anti-influenza A virus drugs that act on conserved sites of novel targets. Here, we found a new anti-influenza virus compound, 1,3-dihydroxy-6-benzo[ c]chromene (D715-2441), from a library of 8026 small-molecule compounds by cell-based MTT assay and explored the underlying mechanisms. Our results revealed that D715-2441 possessed antiviral activities against multiple subtypes of influenza A viruses (IAVs) strains, including H1N1, H5N1, H7N9, H3N2, the clinical isolate 690 (H3), and oseltamivir-resistant strains with the H274Y NA mutation, and suppressed the early steps in the virus replication cycle. Further mechanistic studies indicated that D715-2441 clearly inhibited viral polymerase activity and directly influenced the location of the PB2 protein. Moreover, binding affinity analyses confirmed that D715-2441 bound specifically to the PB2cap protein. Further, protein sequence alignment and a computer-aided molecular docking indicated that highly conserved amino acid residues in the cap-binding pocket of PB2cap were possible binding sites for D715-2441, which indicates that D715-2441 might be employed as a cap-binding competitor. Moreover, the combination of D715-2441 and zanamivir possessed a remarkable synergistic antiviral effect, with an FICI value of 0.40. In conclusion, these results strongly suggest that D715-2441 has potential as a promising candidate against IAV infection. More importantly, our work offers novel options for the strategic development of PB2cap inhibitors of IAV.

Structurally Diverse Polyketides From the Mangrove-Derived Fungus Diaporthe sp. SCSIO 41011 With Their Anti-influenza A Virus Activities.

Influenza A virus (IAV) is a severe worldwide threat to public health and economic development due to its high morbidity and mortality. Marine-derived fungi have been evidenced as a prolific source for the discovery of pharmacologically-active lead compounds. During the course of our search for novel bioactive substances from marine microorganisms, six new polyketides, including two octaketides (1-2), one chromone derivative (13), two highly substituted phthalides (17-18), and one α-pyrone derivative (21) along with 22 known congeners were isolated from a mangrove-associated fungus Diaporthe sp. SCSIO 41011. Their structures were determined by spectroscopic analysis and by comparison with literature data. And the absolute configurations were established according to the specific rotation or electron circular dichroism method. Antiviral evaluation results revealed that compounds 14, 15, 26, and 5-chloroisorotiorin displayed significant anti-IAV activities against three influenza A virus subtypes, including A/Puerto Rico/8/34 H274Y (H1N1), A/FM-1/1/47 (H1N1), and A/Aichi/2/68 (H3N2), with IC50 values in the range of 2.52-39.97 µM. The preliminary structure-activity relationships (SARs) are also discussed. These findings expand the chemical and bioactive diversity of polyketides derived from the genus Diaporthe, and also provide a basis for further development and utilization of chromone, xanthone, and chloroazaphilone derivatives as source of potential anti-viral chemotherapy agents.

The role of oxidative stress in influenza virus infection.

Virus-induced oxidative stress plays an important role in the regulation of the host immune system. In this review, we provide backgrounds of the pathogenic mechanism of oxidative stress induced by influenza virus and the specific oxidant-sensitive pathways, and highlight that antioxidant is one of the effective strategies against influenza virus infection.

Anti-influenza A Virus Activity of Dendrobine and Its Mechanism of Action.

Dendrobine, a major component of Dendrobium nobile, increasingly draws attention for its wide applications in health care. Here we explore potential effects of dendrobine against influenza A virus and elucidate the underlying mechanism. Our results indicated that dendrobine possessed antiviral activity against influenza A viruses, including A/FM-1/1/47 (H1N1), A/Puerto Rico/8/34 H274Y (H1N1), and A/Aichi/2/68 (H3N2) with IC50 values of 3.39 ± 0.32, 2.16 ± 0.91, 5.32 ± 1.68 µg/mL, respectively. Mechanism studies revealed that dendrobine inhibited early steps in the viral replication cycle. Notably, dendrobine could bind to the highly conserved region of viral nucleoprotein (NP), subsequently restraining nuclear export of viral NP and its oligomerization. In conclusion, dendrobine shows potential to be developed as a promising agent to treat influenza virus infection. More importantly, the results provide invaluable information for the full application of the Traditional Chinese Medicine named "Shi Hu".