Polypharmacology of ambroxol in the treatment of COVID-19

The pandemic of coronavirus disease 2019 (COVID-19) by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still underway. Due to the growing development of severe symptoms, it is necessary to promote effective therapies. Ambroxol [2-amino-3,5-dibromo-N-(trans-4-hydroxycyclohexyl) benzylamine] has long been used as one of the over-the-counter mucolytic agents to treat various respiratory diseases. Therefore, we focused on the mechanism of action of ambroxol in COVID-19 treatment. In vitro and in silico screening revealed that ambroxol may impede cell entry of SARS-CoV-2 by binding to neuropilin-1. Ambroxol could also interact with multiple inflammatory factors and signaling pathways, especially nuclear factor kappa B (NF-κB), to interfere cytokines cascade activated by SARS-CoV-2 internalization. Furthermore, multipathways and proteins, such as the cell cycle and matrix metalloproteinases (MMPs), were identified as significant ambroxol-targeting pathways or molecules in PBMC and lung of severe COVID-19 patients by bioinformatics analysis. Collectively, these results suggested that ambroxol may serve as a promising therapeutic candidate for the treatment of severe SARS-CoV-2 infection.