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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel emerging pathogen causing an unprecedented pandemic in 21st century medicine. Due to the significant health and economic burden of the current SARS-CoV-2 outbreak, there is a huge unmet medical need for novel interventions effectively blocking SARS-CoV-2 infection. Unknown details of SARS-CoV-2 cellular biology significantly hamper the development of potent and highly specific SARS-CoV-2 therapeutics. Angiotensin-converting enzyme-2 (ACE2) has been reported to be the primary receptor for SARS-CoV-2 cellular entry. However, emerging scientific evidence suggests the involvement of additional membrane proteins, such as heparan sulfate proteoglycans, in SARS-CoV-2 internalization. Here we report that syndecans, the evolutionarily conserved family of transmembrane proteoglycans facilitate the cellular entry of SARS-CoV-2. Among syndecans, syndecan-4 was the most efficient in mediating SARS-CoV-2 uptake, yet overexpression of other isoforms, including the neuronal syndecan-3, also increased SARS-CoV-2 internalization. The S1 subunit of the SARS-CoV-2 spike protein plays a dominant role in the virus’s interactions with syndecans. Besides the polyanionic heparan sulfate chains - the established binding sites for several viruses - other parts of the syndecan ectodomain, such as the cell-binding domain, also contribute to the interaction with SARS-CoV-2. During virus internalization, syndecans colocalize with ACE2, suggesting a jointly shared internalization pathway. Both ACE2 and syndecan inhibitors exhibited significant efficacy in reducing cellular entry of SARS-CoV-2, thus supporting the complex nature of internalization. Among these inhibitors, a peptide compromising the spike protein’s heparin-binding PRRAR motif significantly reduced SARS-CoV-2 cellular uptake, highlighting the need to go beyond the ACE2 paradigm for developing efficient therapeutics against SARS-CoV-2. Data obtained on syndecan specific in vitro assays present syndecans as novel cellular targets of SARS-CoV-2 and offers molecularly precise, yet simple strategies in overcoming the complex nature of SARS-CoV-2 infection. |
