2. Academic Validation
  3. Exploring 2-methyl-substituted vitamin K3 derivatives with potent inhibitory activity against the 3CL protease of SARS-CoV-2

Exploring 2-methyl-substituted vitamin K3 derivatives with potent inhibitory activity against the 3CL protease of SARS-CoV-2

  • Bioorg Med Chem Lett. 2024 Mar 1:100:129642. doi: 10.1016/j.bmcl.2024.129642.
Ryohto Koharazawa 1,  Mayu Hayakawa 2,  Kazuki Takeda 3,  Kotone Miyazaki 1,  Chisato Tode 4,  Yoshihisa Hirota 2,  Yoshitomo Suhara 5
Affiliations

Affiliations

  • 1 Laboratory of Organic Synthesis and Medicinal Chemistry, Department of Bioscience and Engineering, College of Systems Engineering and Science, Shibaura Institute of Technology, 307 Fukasaku, Minuma-ku, Saitama 337-8570, Japan.
  • 2 Laboratory of Biochemistry, Department of Bioscience and Engineering, College of Systems Engineering and Science, Shibaura Institute of Technology, 307 Fukasaku, Minuma-ku, Saitama 337-8570, Japan.
  • 3 Laboratory of Toxicology, School of Veterinary Medicine, Kitasato University, E23-35-1, Towada, Aomori 034-0021, Japan; Department of Computer Science, Tokyo Institute of Technology, 4259-J3-1818, Nagatsuta-cho, Midori-ku, Yokohama-shi, Kanagawa 226-0026, Japan.
  • 4 Instrumental Analysis Center, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe 658-8558, Japan.
  • 5 Laboratory of Organic Synthesis and Medicinal Chemistry, Department of Bioscience and Engineering, College of Systems Engineering and Science, Shibaura Institute of Technology, 307 Fukasaku, Minuma-ku, Saitama 337-8570, Japan. Electronic address: [email protected].
PMID: 38310976 DOI: 10.1016/j.bmcl.2024.129642
Abstract

Since the outbreak of the pandemic, various anti-SARS-CoV-2 drugs have been developed. In particular, 3CL protease (3C-like protease, 3CLpro) is an attractive drug target because it is an essential Enzyme for viral multiplication and is present only in viruses, not in humans. To date, 3CLpro inhibitors against SARS-CoV-2 such as nirmatrelvir and ensitrelvir have been launched as oral drugs in Japan, but there is still no potent drug against SARS-CoV-2, due to issues of in vivo absorption and stability. Recently, vitamin K3 was reported to show inhibitory activity against 3CLpro of SARS-CoV-2, and the mechanism of action was predicted to be the formation of a covalent bond between the thiol group of cysteine 145, the active center of 3CLpro, and the C-3 position of vitamin K3. Therefore, we synthesized derivatives in which the 2-methyl group of the vitamin K3 was systematically converted to other substituents and examined their inhibitory activity against 3CLpro of SARS-CoV-2. The results showed that the compounds with the sulfide structure showed an approximately 4-fold increase in activity over vitamin K3. These results indicated the possibility of creating new inhibitors based on vitamin K3 and its derivatives.

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