UNI418 is a dual inhibitor of PIKfyve and PIP5K1C with antiviral activity against SARS-CoV-2 ( EC 50 =1.4 μM). UNI418 blocks ACE2-mediated SARS-CoV-2 viral endocytosis by inhibiting PIP5K1C ( IC 50 =60.1 nM; K d =61 nM). In addition, UNI418 inhibits the proteolytic activation of proteases regulated by PIKfyve ( K d =0.78 nM) to prevent SARS-CoV-2 from entering host cells.