UNI418 is a dual inhibitor of PIKfyve and PIP5K1C with antiviral activity against SARS-CoV-2 (EC50=1.4 μM). UNI418 blocks ACE2-mediated SARS-CoV-2 viral endocytosis by inhibiting PIP5K1C (IC50=60.1 nM; Kd=61 nM). In addition, UNI418 inhibits the proteolytic activation of proteases regulated by PIKfyve (Kd=0.78 nM) to prevent SARS-CoV-2 from entering host cells.