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Transferrin receptor is another receptor for SARS-CoV-2 entry

By Xiaopeng Tang, Mengli Yang, Zilei Duan, Zhiyi Liao, Lei Liu, Ruomei Cheng, Mingqian Fang, Gan Wang, Hongqi Liu, Jingwen Xu, Peter M Kamau, Zhiye Zhang, Lian Yang, Xudong Zhao, Xiaozhong Peng, Ren Lai

Posted 23 Oct 2020
bioRxiv DOI: 10.1101/2020.10.23.350348

Angiotensin-converting enzyme 2 (ACE2) has been suggested as a receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry to cause coronavirus disease 2019 (COVID-19). However, no ACE2 inhibitors have shown definite beneficiaries for COVID-19 patients, applying the presence of another receptor for SARS-CoV-2 entry. Here we show that ACE2 knockout dose not completely block virus entry, while TfR directly interacts with virus Spike protein to mediate virus entry and SARS-CoV-2 can infect mice with over-expressed humanized transferrin receptor (TfR) and without humanized ACE2. TfR-virus co-localization is found both on the membranes and in the cytoplasma, suggesting SARS-CoV-2 transporting by TfR, the iron-transporting receptor shuttling between cell membranes and cytoplasma. Interfering TfR-Spike interaction blocks virus entry to exert significant anti-viral effects. Anti-TfR antibody (EC50 16.6 nM) shows promising anti-viral effects in mouse model. Collectively, this report indicates that TfR is another receptor for SARS-CoV-2 entry and a promising anti-COVID-19 target. ### Competing Interest Statement The authors have declared no competing interest.

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