This bis-benzyltetrahydroisoquinoline alkaloid, berbamine (4) potently inhibited the infection of various coronaviruses (e.g., SARS-CoV-2 and MERS-CoV), aviviruses (e.g., JEV, ZIKV, and DENV), and enteroviruses (e.g., EV-A71) in host cells, and protected mice from lethal challenge of JEV, as well as inhibited transient receptor potential mucolipins TRPMLs (Ca2+ permeable non-selective cation channels in endosomes and lysosomes), which compromised the endolysosomal tracking of viral receptors, such as ACE2 and DPP4. The gene discussed is ACE2; the disease is infection.