LAUSR

The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) caused COVID‐19 epidemic is worsening. Binding of the Spike1 protein of SARS‐CoV‐2 with the angiotensin‐converting enzyme 2 (ACE2) receptor mediates entry of the virus into host cells. Many reports show that protein arginine methylation by protein arginine methyltransferases (PRMTs) is important for the functions of these proteins, but it remains unclear whether ACE2 is methylated by PRMTs. Here, we show that PRMT5 catalyses ACE2 symmetric dimethylation at residue R671 (meR671‐ACE2). We indicate that PRMT5‐mediated meR671‐ACE2 promotes SARS‐CoV‐2 receptor‐binding domain (RBD) binding with ACE2 probably by enhancing ACE2 N‐glycosylation modification. We also reveal that the PRMT5‐specific inhibitor GSK3326595 is able to dramatically reduce ACE2 binding with RBD. Moreover, we discovered that meR671‐ACE2 plays an important role in ACE2 binding with Spike1 of the SARS‐CoV‐2 Omicron, Delta, and Beta variants; and we found that GSK3326595 strongly attenuates ACE2 interaction with Spike1 of the SARS‐CoV‐2 Omicron, Delta, and Beta variants. Finally, SARS‐CoV‐2 pseudovirus infection assays uncovered that PRMT5‐mediated meR671‐ACE2 is essential for SARS‐CoV‐2 infection in human cells, and pseudovirus infection experiments confirmed that GSK3326595 can strongly suppress SARS‐CoV‐2 infection of host cells. Our findings suggest that as a clinical phase II drug for several kinds of cancers, GSK3326595 is a promising candidate to decrease SARS‐CoV‐2 infection by inhibiting ACE2 methylation and ACE2‐Spike1 interaction.