2. Academic Validation
  3. Ligand-based design and optimization of tecovirimat derivatives as potent antiviral agents against monkeypox virus

Ligand-based design and optimization of tecovirimat derivatives as potent antiviral agents against monkeypox virus

  • Eur J Med Chem. 2026 Feb 5:303:118447. doi: 10.1016/j.ejmech.2025.118447.
Yuanguang Chen 1,  Sumei Yang 2,  Xingyu Zhou 3,  Hongyang Yi 2,  Dizhen Liang 4,  Guanguan Li 5,  Xiang Liu 2,  Peisen Zheng 4,  Yongqing Liu 4,  Xinshan Deng 6,  Xumu Zhang 7,  Qifan Zhou 8,  Hongzhou Lu 9
Affiliations

Affiliations

  • 1 Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Department of Chemistry, Shenzhen Grubbs Institute and Medi-X Pingshan, Southern University of Science and Technology, Shenzhen, 518000, China; Shenzhen AntiV Pharma Co., Ltd., Shenzhen, Guangdong, 518081, China.
  • 2 Institute for Hepatology, National Clinical Research Centre for Infectious Diseases, The Third People's Hospital of Shenzhen and The Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, 518112, China.
  • 3 Department of Computer Science and Engineering, Southern University of Science and Technology, Shenzhen, 518000, China.
  • 4 Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Department of Chemistry, Shenzhen Grubbs Institute and Medi-X Pingshan, Southern University of Science and Technology, Shenzhen, 518000, China.
  • 5 Shenzhen AntiV Pharma Co., Ltd., Shenzhen, Guangdong, 518081, China.
  • 6 Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha, Hunan, 410219, China.
  • 7 Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Department of Chemistry, Shenzhen Grubbs Institute and Medi-X Pingshan, Southern University of Science and Technology, Shenzhen, 518000, China. Electronic address: zhangxm@sustech.edu.cn.
  • 8 Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Department of Chemistry, Shenzhen Grubbs Institute and Medi-X Pingshan, Southern University of Science and Technology, Shenzhen, 518000, China. Electronic address: zhouqf@sustech.edu.cn.
  • 9 Institute for Hepatology, National Clinical Research Centre for Infectious Diseases, The Third People's Hospital of Shenzhen and The Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, 518112, China. Electronic address: luhongzhou@fudan.edu.cn.
PMID: 41391428 DOI: 10.1016/j.ejmech.2025.118447
Abstract

Among orthopoxviruses, monkeypox virus (MPXV) is currently the most significant human pathogen due to ongoing outbreaks and global spread. Tecovirimat, an FDA-approved Antiviral for orthopoxviruses, inhibits the viral p37 protein essential for viral egress and is used under expanded access for monkeypox treatment. To develop more accessible inhibitors and enhance structure-activity relationship (SAR) research, a new library of tecovirimat derivatives has been designed and synthesized. These compounds underwent phenotype determination to evaluate their Antiviral properties, leading to the identification of C12 (EC50 = 12.14 nM, CC50 = 304.63 μM) as a promising lead compound. C12 demonstrated stable high plasma exposure following oral administration in mice, achieving a bioavailability (F) of 162 % and extensive distribution within the plasma. It also demonstrated low toxicity and good tolerability in mice, with a single dose of 2000 mg/kg or repeated doses of 100 mg/kg once daily for 14 days. Additionally, the P37 protein structure of VACN was employed for molecular docking to investigate potential binding interactions. Computational simulations suggest that C12 targets the same protein as tecovirimat, offering valuable insights for the rational design of next-generation analogs.

Keywords

Molecular dynamics; Monkeypox virus; P37 protein; Tecovirimat derivatives.

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