摘要:SummaryWe report robust SARS-CoV2 neutralizing sdAbs targeting the viral peptides encompassing the polybasic cleavage site (CSP) and in the receptor binding domain (RBD) of the spike (S) protein. Both the sdAbs inhibited infectivity of the CoV2 S protein expressing pseudoviruses (LV-CoV2S). Both anti-CSP and RBD intrabodies (IB) inhibited the output of LV(CoV2 S). Anti-CSP IB altered the proteolytic processing and targeted the viral S protein for degradation. Because of cross-reactive CSPs in the entry mediators, the anti-CSP sdAb neutralizedin vitroandin vivothe infectivity of SARS-CoV2 unrelated viruses such as herpes simplex virus 1 (HSV1) and pestes des petits ruminants virus (PPRV). Conversely, anti-HSV1 and anti-PPRV sera neutralized LV(CoV2 S) owing to the presence of CSP reactive antibodies indicating that a prior infection with such pathogens could impact on the pattern of COVID-19.Graphical abstractDisplay OmittedHighlights•Anti-CSP and anti-RBD sdAb efficiently neutralized LV (SARS-CoV2 S) pseudoviruses•Both intrabodies prevented the biogenesis of SARS-CoV2-S pseudovirions•Anti-CSP sdAb neutralized viruses such as HSV1 and PPRV•Anti-HSV1 and anti-PPRV sera neutralized LV(CoV2 S) pseudovirusesVirology, Immunology, and Drugs,