Curcumin has been reported to exert its anti-SARS-CoV-2 activity by inhibiting the binding of spike receptor-binding domain (RBD) to angiotensin-converting enzyme-2 (ACE2). To identify more potent compounds, we evaluated the antiviral activities of curcumin and its analogs in SARS-CoV-2-infected cells. An artificial intelligence-supported activity prediction system was used to select the compounds, and 116 of the 334 curcumin analogs were proposed to have spike RBD-ACE2 binding inhibitory activity. These compounds were narrowed down to eight compounds for confirmatory studies. Six out of the eight compounds showed antiviral activity with EC50 values of less than 30 µM and binding inhibitory activity with IC20 values of less than 30 µM. Structure-activity relationship analyses revealed that the double bonds in the carbon chain connecting the two phenolic groups were essential for both activities. X-ray co-crystallography studies are needed to clarify the true binding pose and design more potent derivatives.
The pharmacokinetics of novel formulations of curcumin mixed with squalene (CSQU) and of curcumin mixed with docosahexaenoic acid (CDHA) was investigated and compared with a standardized unformulated curcumin extract (StdC) and a solid lipid curcumin particle (SLCP) formulation in a randomized, open-label, crossover study. Ten healthy subjects consumed a single dose of each formulation, and blood samples were collected over 8 h. Plasma concentrations of curcumin, demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC) were measured. The dose-normalized AUC0-8h of curcumin was significantly higher for SLCP (2.2-fold), CSQU (2.3-fold) and CDHA (2.8-fold) than for StdC. The dose-normalized AUC0-8h of DMC and BDMC did not significantly change, but their Tmax was significantly shortened for SLCP, CSQU, and CDHA. In conclusion, compared to StdC, both fish oil formulations, CSQU and CDHA, significantly improved curcumin absorption as well as SLCP, and CDHA was bioequivalent or superior to SLCP. No sex differences were observed in curcumin absorption.
Curcumin has been reported to exert its anti-SARS-CoV-2 activity through multiple mechanisms including inhibition of spike receptor-binding domain (RBD) to angiotensin-converting enzyme-2 (ACE2) binding. To identify more potent compounds, we tested curcumin and its analogs for spike RBD-ACE2 binding inhibitory activity and antiviral activity in SARS-CoV-2-infected cells. An artificial intelligence (AI) -supported activity prediction system was used to select the compounds, and 116 compounds with a docking score range of -8.7 to -4.3 kcal/mol were selected from 334 curcumin analogs. These compounds were narrowed down to 10 compounds, including curcumin, for confirmatory studies. These 10 compounds showed a significant correlation (r s =0.685, P=0.029) between the IC 20 values of spike-RBD-ACE2 binding inhibitory activity and EC 50 values of antiviral activity, indicating that the antiviral activity was mediated by spike RBD-ACE2 binding inhibition. Based on the assumption that the binding site of curcumin and its analogs is different from that of anti-spike RBD antibody drugs, it is expected that these compounds through pharmaceutical or pharmacokinetic modification, or the development of more potent derivatives would contribute to supplementing the antiviral activity of antibodies against SARS-CoV-2.
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