rosmarinic-acid and Influenza--Human

The purpose of this study was to examine the in vivo activity of rosmarinic acid (RA) - a phytochemical with antioxidant, anti-inflammatory, and antiviral properties - against influenza virus (IAV). An antibody-based kinase array and different in vitro functional assays were also applied to identify the mechanistic underpinnings by which RA may exert its anti-IAV activity.. We initially examined the potential efficacy of RA using an in vivo mouse model. A time-of-addition assay and an antibody-based kinase array were subsequently applied to investigate mechanism-of-action targets for RA. The hemagglutination inhibition assay, neuraminidase inhibition assay, and cellular entry assay were also performed.. RA increased survival and prevented body weight loss in IAV-infected mice. In vitro experiments revealed that RA inhibited different IAV viruses - including oseltamivir-resistant strains. From a mechanistic point of view, RA downregulated the GSK3β and Akt signaling pathways - which are known to facilitate IAV entry and replication into host cells.. RA has promising preclinical efficacy against IAV, primarily by interfering with the GSK3β and Akt signaling pathways.

Topics: Animals; Antiviral Agents; Cinnamates; Depsides; Glycogen Synthase Kinase 3 beta; Humans; Influenza A virus; Influenza, Human; Mice; Oseltamivir; Proto-Oncogene Proteins c-akt; Rosmarinic Acid; Virus Replication

Neuraminidase (NA), a major glycoprotein found on the surface of the influenza virus, is an important target for the prophylaxis and treatment of influenza virus infections. Recently, several plant-derived polyphenols, especially caffeic acid analogs, have been reported to exert the inhibitory activity against NA.. Herein, we aimed to investigate the anti-influenza NA activity of caffeic acid and its hydroxycinnamate analogues, rosmarinic acid and salvianolic acid A, in comparison to a known NA inhibitor, oseltamivir.. In vitro MUNANA-based NA inhibitory assay was used to evaluate the inhibitory activity of the three interested hydroxycinnamic compounds towards the influenza NA enzyme. Subsequently, allatom molecular dynamics (MD) simulations and binding free energy calculations were employed to elucidate the structural insights into the protein-ligand complexations.. Rosmarinic acid showed the highest inhibitory activity against NA with the IC50 of 0.40 μM compared to caffeic acid (IC50 of 0.81 μM) and salvianolic acid A (IC50 of >1 μM). From 100-ns MD simulations, the binding affinity, hot-spot residues, and H-bond formations of rosmarinic acid/NA complex were higher than those of caffeic acid/NA model, in which their molecular complexations was driven mainly by electrostatic attractions and H-bond formations from several charged residues (R118, E119, D151, R152, E227, E277, and R371). Notably, the two hydroxyl groups on both phenyl and phenylacetic rings of rosmarinic acid play a crucial role in stabilizing NA through a strongly formed Hbond( s).. Our findings shed light on the potentiality of rosmarinic acid as a lead compound for further development of a potential influenza NA inhibitor.

Topics: Antiviral Agents; Caffeic Acids; Cinnamates; Depsides; Enzyme Inhibitors; Humans; Influenza, Human; Ligands; Molecular Dynamics Simulation; Molecular Structure; Neuraminidase; Rosmarinic Acid; Thermodynamics