Scripps Research scientists conducted a comprehensive siRNA screen to pinpoint host proteins indispensable to SARS-CoV-2 infection, identifying 32 proteins critical in early viral entry and 27 involved in later replication stages. This functional genomic approach highlights pathways such as Wnt signaling and MAPK, offering promising targets for host-directed antivirals with potential activity against multiple coronaviruses, addressing challenges posed by viral mutations and drug resistance. The study underscores a strategic shift toward targeting host-virus interactions to develop broad-spectrum therapies.