Developing therapeutics against SARS-CoV-2 could be guided by the distribution of epitopes, not only on the receptor binding domain (RBD) of the Spike (S) protein, but also across the full Spike (S) protein. We isolated and characterized monoclonal antibodies (mAbs) from ten convalescent COVID-19 patients. Three mAbs showed neutralizing activities against authentic SARS-CoV-2. An mAb, named 4A8, exhibits high neutralization potency against both authentic and pseudotyped SARS-CoV-2, but does not bind the RBD. We defined the epitope of 4A8 as the N terminal domain (NTD) of the S protein by determining its cryo-EM structure in complex with the S protein to an overall resolution of 3.1 Angstrom and local resolution of 3.3 Angstrom for the 4A8-NTD interface. This points to the NTD as a promising target for therapeutic mAbs against COVID-19.

The biogenesis of exosomes, small secreted vesicles involved in signalling processes, remains incompletely understood. Here, we report evidence that the syndecan heparan sulphate proteoglycans and their cytoplasmic adaptor syntenin control the formation of exosomes. Syntenin interacts directly with ALIX through LYPX(n)L motifs, similarly to retroviral proteins, and supports the intraluminal budding of endosomal membranes. Syntenin exosomes depend on the availability of heparan sulphate, syndecans, ALIX and ESCRTs, and impact on the trafficking and confinement of FGF signals. This study identifies a key role for syndecan-syntenin-ALIX in membrane transport and signalling processes.