Antiviral potential of rosuvastatin and hesperidin in combination with favipiravir liposomal nanoformulations in targeting the main protease (M pro ) of SARS-CoV-2: Molecular docking, molecular dynamics and in-vitro studies

Favipiravir (Fav) is a drug utilized to treat coronavirus disease 2019 (COVID-19) due its capacity to expedite the clearance of the SARS-CoV-2 virus through binding to its main protease (M pro ). However, the use of Fav has been associated with some adverse health effects. Meanwhile, numerous studies have highlighted the potential antiviral activities of specific phytochemicals and statins. Consequently, we thought to explore drug combination strategies involving certain statins and phytochemicals and their liposome nanoformulations either alone or with Fav, aiming to augment its efficacy and mitigate potential adverse effects. The molecular docking and molecular dynamic simulations analyses have revealed that hesperidin (HES) and rosuvastatin (ROS) have the best targeting potential for M pro protein out of 10 phytochemicals and 6 statin compounds. The selected compounds were elaborated alone or with FAV into six nanoformulations FAV, ROS, HES, FAV/ROS, FAV/HES, and FAV/ROS/HES-loaded liposomes. Light and electron microscope evaluations confirmed the vesicular shape of all liposomal dispersions. The entrapment capacity and release extent from FAV/ROS/HES-loaded liposomes was the lowest compared to other nanoformulations. In vitro, the FAV/HES or FAV/ROS-loaded liposomes displayed the highest capacity to impede the replication of SARS-CoV-2 with IC50 of 0.738 and 3.28 μg/mL, respectively. These results confirmed the potential of hesperidin and rosuvastatin as adjuvant medications with Favipiravir to combat COVID-19 and suggest the preference of the combinatory treatments. Finally, our findings provide a rational for further in-vivo studies to evaluate the potential activities of these drug combinations to mitigate the adverse events of favipiravir and to boost its SARS-CoV-2 clearance efficacy.