J Med Virol . GSK3326595 is a promising drug to prevent SARS-CoV-2 Omicron and other variants infection by inhibiting ACE2-R671 di-methylation

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J Med Virol


. 2022 Sep 16.
doi: 10.1002/jmv.28158. Online ahead of print.
GSK3326595 is a promising drug to prevent SARS-CoV-2 Omicron and other variants infection by inhibiting ACE2-R671 di-methylation


Zhongwei Li ^{1 2} , Hongmei Yong ³ , Wenwen Wang ¹ , Yue Gao ¹ , Pengfei Wang ¹ , Xintian Chen ¹ , Jun Lu ⁴ , Junnian Zheng ^{1 2} , Jin Bai ^{1 2}



Affiliations

• PMID: 36114164
• DOI: 10.1002/jmv.28158

Abstract

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 ACE2 receptor mediates entry of the virus into host cells. Many reports show that protein arginine methylation by 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 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. This article is protected by copyright. All rights reserved.

Keywords: ACE2; Arginine Methylation; PRMT5; RBD; SARS-CoV-2.