This study identifies 332 high-confidence host-pathogen protein-protein interactions (PPIs) between SARS-CoV-2 and human proteins. The focus is on prey proteins involved in comorbidities and those connected to other viral infections or viral protein interactions. Evolutionary analysis reveals 40 prey proteins that evolved under recurrent positive selection in simian primates, suggesting potential hijacking by different pathogens. The study provides detailed reviews of principal interactions for each bait, including structural and non-structural proteins, and their potential roles in viral infection and pathogenesis. Interactive network maps and data tables are available online to facilitate research and drug repurposing efforts. Key interactions are highlighted, such as the spike protein's interaction with the GOLGA7-ZDHHC5 complex, which may be a target for therapeutic intervention. The study also discusses the potential implications of host factors like BRD2/BRD4, CK2, and LARP1 in viral replication and immune response modulation.This study identifies 332 high-confidence host-pathogen protein-protein interactions (PPIs) between SARS-CoV-2 and human proteins. The focus is on prey proteins involved in comorbidities and those connected to other viral infections or viral protein interactions. Evolutionary analysis reveals 40 prey proteins that evolved under recurrent positive selection in simian primates, suggesting potential hijacking by different pathogens. The study provides detailed reviews of principal interactions for each bait, including structural and non-structural proteins, and their potential roles in viral infection and pathogenesis. Interactive network maps and data tables are available online to facilitate research and drug repurposing efforts. Key interactions are highlighted, such as the spike protein's interaction with the GOLGA7-ZDHHC5 complex, which may be a target for therapeutic intervention. The study also discusses the potential implications of host factors like BRD2/BRD4, CK2, and LARP1 in viral replication and immune response modulation.