Pseudoephedrine and its derivatives antagonize wild and mutated severe acute respiratory syndrome‐CoV‐2 viruses through blocking virus invasion and antiinflammatory effect

The coronavirus disease 2019 has infected over 150 million people worldwide and led to over 3 million deaths. Severe acute respiratory syndrome (SARS)‐CoV‐2 lineages B.1.1.7, B.1.617, B.1.351, and P.1 were reported to have higher infection rates than that of wild one. These mutations were noticed to happen in the receptor‐binding domain of spike protein (S‐RBD), especially mutations N501Y, E484Q, E484K, K417N, K417T, and L452R. Currently, there is still no specific medicine against the virus; moreover, cytokine storm is also a dangerous factor for severe infected patients. In this study, potential S‐RBD‐targeted active monomers from traditional Chinese medicine Ephedra sinica Stapf (ephedra) were discovered by virtual screening. NanoBiT assay was performed to confirm blocking activities of the screened compounds against the interaction between SARS‐CoV‐2 S‐RBD and angiotensin‐converting enzyme 2 (ACE2). We further analyzed the blocking effect of the active compounds on the interactions of mutated S‐RBD and ACE2 by computational studies. Moreover, antiinflammatory activities were evaluated using qRT‐PCR, enzyme‐linked immune sorbent assay, and Western blot analysis. As a result, pseudoephedrine (MHJ‐17) and its derivative (MHJ‐11) were found as efficient inhibitors disrupting the interactions between ACE2 and both wild and mutated S‐RBDs. In addition, they also have antiinflammatory activities, which can be potential drug candidates or lead compounds for further study.