curcumin and petasiphenol

Curcumin (Cur) is a commonly used colouring agent and spice in food. Previously, we reported that Cur inhibits type A influenza virus (IAV) infection by interfering with viral haemagglutination (HA) activity. To search for a stable Cur analogue with potent anti-IAV activity and to investigate the structure contributing to its anti-IAV activity, a comparative analysis of structural and functional analogues of Cur, such as tetrahydrocurcumin (THC) and petasiphenol (Pet), was performed. The result of time-of-drug addition tests indicated that these curcuminoids were able to inhibit IAV production in cell cultures. Noticeably, Pet and THC inhibit IAV to a lesser extent than Cur, which is in line with their effect on reducing plaque formation when IAV was treated with Cur analogues before infection. Unexpectedly, both THC and Pet did not harbour any HA inhibitory effect. It should be noted that the structure of Pet and THC differs from Cur with respect to the number of double bonds present in the central seven-carbon chain, and structure modelling of Cur analogues indicates that the conformations of THC and Pet are distinct from that of Cur. Moreover, simulation docking of Cur with the HA structure revealed that Cur binds to the region constituting sialic acid anchoring residues, supporting the results obtained by the inhibition of HA activity assay. Collectively, structure-activity relationship analyses indicate that the presence of the double bonds in the central seven-carbon chain enhanced the Cur -dependent anti-IAV activity and also that Cur might interfere with IAV entry by its interaction with the receptor binding region of viral HA protein.

Topics: Animals; Antiviral Agents; Binding Sites; Caffeic Acids; Curcumin; Dogs; Glutathione; Glutathione Disulfide; Hemagglutinin Glycoproteins, Influenza Virus; Humans; Influenza A virus; Madin Darby Canine Kidney Cells; Models, Molecular; Molecular Conformation; Protein Conformation; Structure-Activity Relationship; Viral Plaque Assay

We previously reported that a phenolic compound, petasiphenol, was a selective inhibitor of DNA polymerase lambda (pol lambda) in vitro. We found here that another phenolic compound, curcumin (diferuloylmethane), which is known as an anti-chronic inflammatory agent and is structurally quite similar to petasiphenol, was also a potent pol lambda inhibitor. The IC(50) values of petasiphenol and curcumin were 7.8 and 7.0 microM, respectively. Curcumin, as well as petasiphenol, did not influence the activities of replicative DNA polymerases, such as alpha, gamma, delta, and epsilon, but also showed no effect even on the pol beta activity belonging to the X family. Curcumin could prevent the growth of human NUGC-3 cancer cells with LD(50) values of 13 microM, and halted them at the G2/M phase in the cell cycle, whereas petasiphenol suppressed the cell growth at 66 microM and arrested the cells at the G1 phase. These data showed that curcumin and petasiphenol were slightly different functionally. We also previously reported that novel anti-inflammatory terpeno benzoic acids and triterpenoids were inhibitors of mammalian DNA polymerases. They could also efficiently inhibit the pol lambda activity, although they influenced the other polymerase species to the same extent, suggesting that there may be a physiological relationship between pol lambda inhibition and anti-12-O-tetradecanoylphorbol-13-acetate-induced inflammation. Expectedly, petasiphenol also showed an anti-12-O-tetradecanoylphorbol-13-acetate-induced inflammatory effect in mice. This finding may provide clues to investigating the molecular mechanism of inflammation.

Topics: Animals; Anti-Inflammatory Agents; Caffeic Acids; Cell Division; Curcumin; DNA Polymerase beta; Enzyme Inhibitors; Humans; Inflammation; Mice; Phenols; Tetradecanoylphorbol Acetate