In summary, this is the first demonstration that S1 binding to ACE2 induces enzyme internalization through clathrin-coated pits, followed by lysosomal degradation, as previously reported by our group for Ang II. 3 This process requires AT1R expression and higher AT1R levels potentiate the internalization of S1, component of SARS-CoV-2 envelope. One can envision that S1 stimulates the formation of AT1R/ACE2 complexes which are required for enzyme internalization, but further experiments are required to validate this hypothesis. Blockade of lysosomal function by leupeptin or hydroxychloroquine fully prevented the effects of S1 on ACE2 internalization and degradation. Importantly from a clinical point of view, our cellular experiments strongly indicate that losartan, an extensively used antihypertensive drug, blocked ACE2 internalization induced by S1. Therefore, unlike initial concerns, 2 the use of AT1R blockers in COVID-19 may produce unexpected benefits. However, clinical studies are necessary to confirm these in vitro results.