Curcuminoid Analogues As Novel Neuraminidase Inhibitors For Influenza A (H1N1) Virus Infection

Azman, Siti Arfa Raziah (2022) Curcuminoid Analogues As Novel Neuraminidase Inhibitors For Influenza A (H1N1) Virus Infection. [Project Paper] (Submitted)

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Abstract

Influenza A virus (IAV) infection poses a significant risk of asthma exacerbation and respiratory diseases. Neuraminidase (NA) inhibitors are the primary treatment for IAV infections; however, NA protein mutations require the development of novel antiviral drugs. Although curcumin has been proven to exhibit various pharmacological properties, including anti-IAV effects, its limited water solubility and systemic absorption restrict its therapeutic efficacy. Structurally modified curcuminoid analogues, particularly 5-(3,4-dihydroxyphenyl)-3-hydroxy-1-(2-hydroxyphenyl)penta-2,4-dien-1-one (DHHPD) and 2-benzoyl-6-(3,4-dihydroxybenzylidene)cyclohexen-1-ol (BDHBC), have higher water solubility and more potent anti-inflammatory effect compared to curcumin. A previous study demonstrated that curcumin inhibited both NA activity and IAV replication. Thus, we hypothesised that the curcuminoid analogues, DHHPD and BDHBC, may also target NA to inhibit IAV replication. Objective: This study aims to evaluate the antiviral activity of the curcuminoid analogues (BDHBC and DHHPD) against IAV (H1N1) and their potential inhibitory effect on NA, a crucial enzyme in the IAV replication process. Methodology: A549 cells were infected with influenza A/Puerto Rico/8/1934 H1N1 (PR8) for one hour and subsequently treated with non-cytotoxic concentrations of curcumin, BDHBD and DHHPD (5, 10 and 20µM). The levels of infectious viral particles in the culture supernatants of A549 cells were determined using 50% Tissue Culture Infectious Dose (TCID50) assay. As the NA protein structure of IAV PR8 is unavailable in the Protein Data Bank (PDB), a homology model was constructed using the SWISS-MODEL platform. The NA homology model was then used to perform molecular docking using the Discovery Studio 2016 software to predict and compare the binding positions of curcumin, BDHBC and DHHPD on the active site of NA protein. Results: TCID50 assay revealed that DHHPD and BDHBC significantly reduced the levels of infectious viral particles released by IAV-infected A549 cells. The largest reduction was shown by DHHPD (20µM), followed by curcumin (20µM) and BDHBC (20µM). The antiviral effect of DHHPD was significantly higher than BDHBC (p<0.05), but there was no significant difference between DHHPD and curcumin. Molecular docking using the NA homology model showed that DHHPD had the strongest binding affinity to NA with the lowest CDOCKER energy value (-58.4931 kcal/mol), followed by curcumin (-39.0365 kcal/mol), and BDHBC (-5.56237 kcal/mol). Discussion: When used as a post-treatment for IAV-infected A549 cells, the curcuminoid analogues (DHHPD and BDHBC) exhibited significant antiviral activity, indicating that they may also inhibit IAV replication like curcumin. Consistent with this finding, molecular docking also showed that DHHPD has the highest binding affinity to NA. This suggests that the antiviral effect of DHHPD may be due to its potential binding to the active site of NA which subsequently inhibits its function for new virion release. Conclusion: Curcuminoid analogues, particularly DHHPD, may be a novel neuraminidase inhibitor for IAV infection. Future study using enzymatic assay is needed to confirm its inhibitory effect on NA.

Item Type:	Project Paper
Faculty:	Faculty of Medicine and Health Science
Depositing User:	Ms. Nor Safa'aton Saidin
Date Deposited:	22 Aug 2023 04:39
Last Modified:	22 Aug 2023 04:39
URI:	http://psaspb.upm.edu.my/id/eprint/1364

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