Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) first surfaced in the end of 2019. It is a highly transmissible and dangerous coronavirus. It has brought upon us a pandemic of acute respiratory illness known as COVID-19, which poses a risk to both human health and public safety (1). This virus has a spike protein on its surface, which is the key to its entry into host cells. This spike protein has two subunits: S1 and S2. It also has two different protease cleavage sites, one in between the two subunits called the S1/S2 cleavage site which is cleaved by furin (2). And the second one in the S2 subunit called S2’, is cleaved by transmembrane serine protease-2 (TMPRSS2) on the cell surface or cathepsin L in the endosome (3). The spike protein binds to angiotensin-converting enzyme 2 (ACE2) receptor post furin cleavage to enter the cells (4). Researchers have shown that cells devoid of this receptor were also susceptible to SARS-CoV-2 infection (5,6). We wanted to find new host cell surface proteins that are involved in SARS-CoV-2 entry. The environment of the SARS-CoV-2 virion during entry is still not fully understood, hence the importance of the study. Based on a short list of target proteins identified with a cell surface proximity ligation assay, we used a CRISPR-Cas9 knockout approach, and identified six proteins: AXL, PROM1, LY75, F3, ERBB2 and ICAM1 as potential inhibitors of SARS-CoV-2 entry. Moreover, by performing genetic overexpression of these proteins, we observed that ERBB2 overexpression led to a reduction in viral entry, making it more likely that this protein will function an inhibitor of entry. We detected a decrease in the expression of the S2 subunit during the co-transfection of AXL, PROM1 and LY75 with the spike protein. Therefore, these proteins might be potential inhibitors of the furin cleavage process. We can conclude that ERBB2 could be a potential inhibitor of SARS-CoV-2 entry and that AXL, PROM1 and LY75 might be involved in the furin cleavage of spike, but we still need to investigate the underlying mechanisms.