Identification of Vitamin K3 and its analogues as covalent inhibitors of SARS-CoV-2 3CL pro

• Published in: International journal of biological macromolecules Vol. 183; p. 182
• Main Authors: Wang, Ruyu, Hu, Qing, Wang, Haonan, Zhu, Guanghao, Wang, Mengge, Zhang, Qian, Zhao, Yishu, Li, Chunyu, Zhang, Yani, Ge, Guangbo, Chen, Hongzhuan, Chen, Lili
• Format: Journal Article
• Language: English
• Published: Netherlands 31-07-2021
• Subjects: Coronavirus 3C Proteases - antagonists & inhibitors; Coronavirus 3C Proteases - chemistry; COVID-19 Drug Treatment; Cysteine Proteinase Inhibitors - chemistry; Cysteine Proteinase Inhibitors - therapeutic use; Humans; SARS-CoV-2 - enzymology; Vitamin K 3 - analogs & derivatives; Vitamin K 3 - chemistry; SARS-CoV-2 3CL(pro); Covalent inhibitors; Vitamin K3
• ISSN: 1879-0003

After the emergence of the pandemic, repurposed drugs have been considered as a quicker way of finding potential antiviral agents. SARS-CoV-2 3CL
is essential for processing the viral polyproteins into mature non-structural proteins, making it an attractive target for developing antiviral agents. Here we show that Vitamin K3 screened from the FDA-Approved Drug Library containing an array of 1,018 compounds has potent inhibitory activity against SARS-CoV-2 3CL
with the IC
value of 4.78 ± 1.03 μM, rather than Vitamin K1, K2 and K4. Next, the time-dependent inhibitory experiment was carried out to confirm that Vitamin K3 could form the covalent bond with SARS-CoV-2 3CL
. Then we analyzed the structure-activity relationship of Vitamin K3 analogues and identified 5,8-dihydroxy-1,4-naphthoquinone with 9.8 times higher inhibitory activity than Vitamin K3. Further mass spectrometric analysis and molecular docking study verified the covalent binding between Vitamin K3 or 5,8-dihydroxy-1,4-naphthoquinone and SARS-CoV-2 3CL
. Thus, our findings provide valuable information for further optimization and design of novel inhibitors based on Vitamin K3 and its analogues, which may have the potential to fight against SARS-CoV-2.