Secretory full-length human prosaposin (PSAP) inhibits SARS-CoV-2 infection through facilitating the release of S1 subunit of spike protein

The systematic identification of host factors that modulate SARS-CoV-2 infection is critical for elucidating the mechanisms of virus-host interaction and for advancing the development of novel host-directed therapeutic interventions. In this study, we identify the human protein prosaposin (PSAP) as a novel and potent innate restriction factor that effectively blocks SARS-CoV-2 infection. By binding with high affinity to the spike protein's receptor-binding domain (RBD) at a unique site, PSAP neutralizes the virus, thereby preventing cellular entry. Consequently, this discovery establishes a foundation for a novel host-directed therapeutic strategy. The development of pharmacologic agents that recapitulate PSAP's action could yield a new class of antivirals that neutralize SARS-CoV-2 by mechanistically disrupting spike protein integrity, offering a complementary approach to conventional antibody therapies.