2. Academic Validation
  3. Thiol esters as chemical warheads of SARS-CoV-2 main protease (3CLpro) peptide-like inhibitors

Thiol esters as chemical warheads of SARS-CoV-2 main protease (3CLpro) peptide-like inhibitors

  • Eur J Med Chem. 2025 May 8:293:117709. doi: 10.1016/j.ejmech.2025.117709.
Xuehong Qiao 1,  Menghan Cui 2,  Zhiwei Yu 3,  Ling Ma 4,  Hailong Liu 5,  Xingxing Yang 6,  Yuan Chen 7,  Dahong Li 8,  Jinjing Che 9,  Linxiang Zhao 10,  Ruibin Su 11,  Xuhong Ren 12,  Shan Cen 13,  Bin Lin 14,  Xinhua He 15
Affiliations

Affiliations

  • 1 Shenyang Pharmaceutical University, Wenhua Road 103#, Shenyang, 110016, China; Beijing Institute of Pharmacology and Toxicology, Taiping Road 27#, Haidian District, Beijing, 100850, China. Electronic address: 2419571918@qq.com.
  • 2 Shenyang Pharmaceutical University, Wenhua Road 103#, Shenyang, 110016, China; Beijing Institute of Pharmacology and Toxicology, Taiping Road 27#, Haidian District, Beijing, 100850, China. Electronic address: cui1421741355@163.com.
  • 3 Shenyang Pharmaceutical University, Wenhua Road 103#, Shenyang, 110016, China. Electronic address: yuzhiwei0519@163.com.
  • 4 Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Tiantan Xili 1#, Dongcheng District, Beijing, 100050, China. Electronic address: maling26@imb.pumc.edu.cn.
  • 5 Shenyang Pharmaceutical University, Wenhua Road 103#, Shenyang, 110016, China; Beijing Institute of Pharmacology and Toxicology, Taiping Road 27#, Haidian District, Beijing, 100850, China. Electronic address: 17835855878@163.com.
  • 6 Shenyang Pharmaceutical University, Wenhua Road 103#, Shenyang, 110016, China; Beijing Institute of Pharmacology and Toxicology, Taiping Road 27#, Haidian District, Beijing, 100850, China. Electronic address: yxxest@163.com.
  • 7 Nanhu Laboratory, National Center of Biomedical Analysis, Beijing, 100039, China. Electronic address: ychen@ncba.ac.cn.
  • 8 Shenyang Pharmaceutical University, Wenhua Road 103#, Shenyang, 110016, China. Electronic address: lidahong0203@163.com.
  • 9 Beijing Institute of Pharmacology and Toxicology, Taiping Road 27#, Haidian District, Beijing, 100850, China. Electronic address: chejinjing80@126.com.
  • 10 Shenyang Pharmaceutical University, Wenhua Road 103#, Shenyang, 110016, China. Electronic address: zhaolinxiang@syphu.edu.cn.
  • 11 Beijing Institute of Pharmacology and Toxicology, Taiping Road 27#, Haidian District, Beijing, 100850, China. Electronic address: suruibin@126.com.
  • 12 Shenyang Pharmaceutical University, Wenhua Road 103#, Shenyang, 110016, China. Electronic address: renxuhong2003@163.com.
  • 13 Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Tiantan Xili 1#, Dongcheng District, Beijing, 100050, China. Electronic address: shancen@imb.pumc.edu.cn.
  • 14 Shenyang Pharmaceutical University, Wenhua Road 103#, Shenyang, 110016, China.
  • 15 Beijing Institute of Pharmacology and Toxicology, Taiping Road 27#, Haidian District, Beijing, 100850, China; Nanhu Laboratory, National Center of Biomedical Analysis, Beijing, 100039, China. Electronic address: hexinhua01@126.com.
PMID: 40344734 DOI: 10.1016/j.ejmech.2025.117709
Abstract

Peptide-like 3CLpro covalent binding inhibitors are the most effective Antiviral drugs for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Infection. Their covalent warheads were designed based on the addition reaction activity of the aldehyde (ketone) carbonyl or its derivative structures. These addition reactions between the warheads and the thiol of the 3CLpro are reversible, and the resulting hemimonothioacetals are chemically unstable. Herein, after DFT calculation, we designed thiol ester warheads using the principle of ester exchange reaction. Then, the warhead fluorescence probe binding experiment suggested these adducts of thiol ester warheads and 3CLpro protein are more stable than the hemimonothioacetals mentioned earlier. Therefore, new 3CLpro inhibitors were subsequently designed through a structure-based drug design method employing those thiol ester warheads. Those 3CLpro inhibitors demonstrated potent 3CLpro inhibitory activities and anti-coronavirus HCoV-OC43 activities. Among them, B16 stands out as the most promising, demonstrating not only the strongest anti-coronavirus HCoV-OC43 activity but also being a moderate inhibitor of CYP3A4, suggesting that B16 does not require co-administration with ritonavir in the treatment of SARS-CoV-2 Infection. This work demonstrates the significant potential of thiol esters as novel chemical warheads in designing covalent binding inhibitors for 3CLpro and beyond.

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