Researchers at Scripps Research performed a global siRNA screen identifying key human host factors essential for SARS-CoV-2’s replication cycle. The study differentiated proteins used in early and late infection stages and uncovered novel cellular pathways exploited by the virus, including Wnt signaling, NADH oxidation, and arachidonate production. Two proteins, perlecan and others, emerged as promising drug targets due to their interaction with viral components. This host-targeting strategy promises pan-coronavirus therapeutic options with reduced vulnerability to viral mutations and resistance, representing a paradigm shift in antiviral drug development.