2. Academic Validation
  3. Identification of Vitamin K3 and its analogues as covalent inhibitors of SARS-CoV-2 3CLpro

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

  • Int J Biol Macromol. 2021 Jul 31:183:182-192. doi: 10.1016/j.ijbiomac.2021.04.129.
Ruyu Wang 1,  Qing Hu 1,  Haonan Wang 1,  Guanghao Zhu 1,  Mengge Wang 1,  Qian Zhang 2,  Yishu Zhao 1,  Chunyu Li 1,  Yani Zhang 1,  Guangbo Ge 3,  Hongzhuan Chen 4,  Lili Chen 5
Affiliations

Affiliations

  • 1 Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • 2 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
  • 3 Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: [email protected].
  • 4 Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: [email protected].
  • 5 Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: [email protected].
PMID: 33901557 DOI: 10.1016/j.ijbiomac.2021.04.129
Abstract

After the emergence of the pandemic, repurposed drugs have been considered as a quicker way of finding potential Antiviral agents. SARS-CoV-2 3CLpro 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 3CLpro with the IC50 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 3CLpro. 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 3CLpro. 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.

Keywords

Covalent inhibitors; SARS-CoV-2 3CL(pro); Vitamin K3.

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