In a recent study published in the journal Viruses, researchers evaluated the effectiveness of flavonols in inhibiting coronavirus 2 (SARS-CoV-2) from severe acute respiratory syndrome.
Study: Commercially available flavonols are better inhibitors of SARS-CoV-2 than isoflavones and flavones. Image credit: clobatot / Shutterstock
Although vaccines against coronavirus disease 2019 (COVID-19) have greatly slowed the transmission of SARS-CoV-2, there is still an urgent need for anti-SARS-CoV-2 compounds. Interestingly, flavonoids, a class of natural polyphenols commonly found in vegetables and fruits, are popularly investigated for their potential as a method of treating various diseases. It is also often used as a scaffold during the development of new drugs.
About the study
In the present study, the researchers evaluated seven flavonoids, classified into three subclasses, flavonols that include fisetin, myricetin, kaempferol, and quercetin, flavones that include luteolin and apigenin, and isoflavones that include genistein for the treatment of COVID-19.
The team examined fisetin, myricetin, kaempferol, quercetin, luteolin, apigenin, and genistein for their ability to inhibit SARS-CoV-2 replication through cell-based assays. Subsequently, according to a study that studied all proteins that played an essential role in the pathogenicity of SARS-CoV-2, the team performed molecular coupling studies on the glycoprotein (S) of the SARS-Co CoV-2 with a receptor binding domain (RBD). ).
This molecular coupling analysis was performed both in the presence and absence of the angiotensin-2-converting enzyme (ACE-2), as it played an important role in the entry of SARS-CoV-2 and papain-like protease (PLpro) and primary protease (Mpro) as they were essential in the maturation and division of SARS-CoV-2 polyproteins. For the in silico evaluation of SARS-CoV-2 ExoN, a molecular coupling analysis was performed on two different enzymatic 3D structures that differ in the number of cofactor magnesium ions present in the catalytic pocket.
Results
The results of the study showed that the values of 50% effective concentration (EC50) of flavonols were lower than those of flavones and isoflavones. Among flavonols, the EC50 values of myricetin were 0.91 ± 0.05 μM while that of fisetin was 2.03 ± 0.10 μM, suggesting that these two compounds were potential candidates for effective inhibition of SARS-CoV-2 replication. In addition, the 50% cytotoxic concentration (CC50) for most natural products tested was 60 times higher than the corresponding EC50 values. This showed a selective index (SI) that was consistent with an efficient safety profile, especially for myricetin which had an SI value of 787.
Cell-based assays showed that only genistein reduced levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), while other flavonoids only affected TNF-α. In addition, molecular coupling studies showed that RNA polymerase (RdRp) is dependent on ribonucleic acid (RNA), which is essential for viral genomic replication, and exoribonuclease (ExoN), which had an important role in the correction of genomic tests, they had magnesium ions in their catalytic pockets.
Previous studies have indicated that the biological function of flavonoids could interact with magnesium ions and cause inhibition of human immunodeficiency virus (HIV) integrase. This suggested that SARS-CoV-2 ExoN and RdRp could also be potential targets during in silico evaluation.
In addition, coupling score values for all flavonoids were estimated. A more positive coupling score indicated better interactions in cell-based assays. In the present study, the coupling score suggested that all potential targets evaluated could show interactions with flavonoids. However, the team observed that the coupling scores corresponding to SARS-CoV-2 RdRp, spike, and PLpro proteins were lower than those of SARS-CoV-2 Mpro and ExoN. This indicated that the Mpro and ExoN proteins could be the main targets of flavonoids.
The team noted that replacing one of the two magnesium ions found at the catalytic site of the ExoN protein improved the binding capacity of the natural products tested. Flavonols, including fisetin, myricetin, kaempferol, and quercetin, showed a higher coupling score than isoflavones such as genistein, flavones such as luteolin and apigenin, and flavonols such as myricetin and the fisetina. In addition, fisetin and myricetin were the best candidates for SARS-CoV-2 ExoN inhibition.
The observed interactions between SARS-CoV-2 Mpro and flavonoids showed a better fit when there was a substrate rather than absence, suggesting a mechanism involving noncompetitive inhibition. Of all the flavonoids tested, myricetin and fisetin showed the highest coupling scores, suggesting that SARS-CoV-2 Mpro could be a feasible target for both natural products.
Conclusion
The results of the study showed that flavonols fisetin and myricetin proved to be the best candidates for inhibition of SARS-CoV-2 and its anti-inflammatory effects. Researchers believe that the affordability of flavonoids could encourage poor populations to cultivate these plants for later extraction of therapeutic compounds.
Magazine reference:
- Chaves, OA; Fintelman-Rodrigues, N .; Wang, X .; Sacramento, CQ; Temerozo, JR; Ferreira, AC; Mattos, M .; Pereira-Dutra, F .; Bozza, PT; Castro-Faria-Neto, HC; Russo, JJ; Ju, J .; Souza, TML (2022). Commercially available flavonols are better inhibitors of SARS-CoV-2 than isoflavones and flavones. Virus. two: