Screening SARS-CoV-2 main protease inhibitory activity of herbal extracts and development of alpha-mangostin loaded polymeric micelles

Abstract

The coronavirus disease 19 (COVID-19) is an infectious disease. The outbreak of COVID-19 that emerged in December 2019 has caused a serious pandemic and detrimental impacts on people worldwide. Both vaccinations and treatments are needed to achieve the comprehensive level of health care against COVID-19. Several novel vaccines and drugs have been discovered and developed, but the problem has not been fully resolved due to their associated adverse effects. Since traditional herbal medicines have been used for many years in various disease treatments due to their safety and efficacy, developing natural product-based drugs could be one of the most promising strategies. Some of the bioactive compounds from Thai herbs have been reported recently for their potential inhibitory activity towards SARS-CoV-2 main protease (3CLPro), which is a key enzyme for viral replication. Hence, this study aims to investigate the potential 3CLPro inhibitor from herbal extracts by an in vitro screening. The results showed that turmeric rhizome, licorice root, sweet fennel seeds and long pepper fruits had promising 3CLPro inhibitory activity. It was also investigated that the pericarp extract of mangosteen fruit had the highest in vitro 3CLPro inhibitory activity. Alpha-mangostin which is the most studied natural xanthone from mangosteen pericarp extract has been selected as the interested bioactive compound in this study to further evaluate its potential SARS-CoV-2 main protease inhibitory activity. In order to improve the solubility and bioavailability, alpha-mangostin was encapsulated in Soluplus® polymeric micelles. Based on the preliminary results, 5% w/w alpha-mangostin loaded polymeric micelles prepared with Soluplus® concentration of 1 mg/mL seemed to be the promising formulation due to its high encapsulation efficiency and loading capacity. Then, higher Soluplus® concentrations and higher alpha-mangostin concentrations were used to investigate further for higher encapsulation efficiency, loading capacity and the other characterization parameters. It was investigated that the 5%w/w formulation which was made up of 10 mg/mL Soluplus® and 0.5 mg/mL alpha-mangostin, was the promising formulation in terms of the highest encapsulation efficiency and loading capacity as well as the desirable characterizations results. The spherical shape of both blank Soluplus® polymeric micelles and alpha-mangostin loaded Soluplus® polymeric micelles was noted from TEM analysis. Regarding the stability, the formulation kept at 4°C seemed to be more stable as compared to the one kept at room temperature. Although the percent (%) inhibition of alpha-mangostin loaded polymeric micelles towards 3CLPro was lower than that of alpha-mangostin compound without the nanocarrier, it could still be considered as the promising formulation because its % inhibition towards 3CLPro was more than 50%. Moreover, alpha-mangostin loaded in polymeric micelles displayed higher %cell viability than alpha-mangostin compound without the nanocarrier. Overall, alpha-mangostin can be loaded in Soluplus® polymeric micelles with high efficiency, and it showed the promising results towards SARS-CoV-2 main protease (3CLPro) inhibitory activity with lower cytotoxicity which will be useful for further studies.