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  3. Discovery of peptidomimetic spiropyrrolidine derivatives as novel 3CLpro inhibitors against SARS-CoV -2

Discovery of peptidomimetic spiropyrrolidine derivatives as novel 3CLpro inhibitors against SARS-CoV -2

  • Eur J Med Chem. 2024 Oct 28:281:117004. doi: 10.1016/j.ejmech.2024.117004.
Samuel Desta Guma 1,  Zhaoyin Zhou 2,  Kang Song 3,  Feipu Yang 4,  Jin Suo 4,  Yan Zhang 4,  Emmanuel Mintah Bonku 1,  Abdullajon Odilov 1,  Guanghui Tian 5,  Zhijian Xu 6,  Xiangrui Jiang 7,  Qiumeng Zhang 8,  Weiliang Zhu 9,  Jingshan Shen 10
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, 201203, Shanghai, PR China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, 100049, Beijing, PR China.
  • 2 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 210023, Nanjing, PR China; State Key Laboratory of Drug Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, 201203, Shanghai, PR China.
  • 3 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 210023, Nanjing, PR China.
  • 4 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, 201203, Shanghai, PR China.
  • 5 Vigonvita Life Science Co., Ltd., 108 Yuxin Road, Suzhou Industrial Park, 215123, Suzhou, Jiangsu, PR China.
  • 6 State Key Laboratory of Drug Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, 201203, Shanghai, PR China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, 100049, Beijing, PR China.
  • 7 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, 201203, Shanghai, PR China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, 100049, Beijing, PR China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, 264117, Yantai, Shandong, PR China.
  • 8 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, 201203, Shanghai, PR China. Electronic address: qmzhang@simm.ac.cn.
  • 9 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 210023, Nanjing, PR China; State Key Laboratory of Drug Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, 201203, Shanghai, PR China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, 100049, Beijing, PR China. Electronic address: wlzhu@simm.ac.cn.
  • 10 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, 201203, Shanghai, PR China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 210023, Nanjing, PR China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, 100049, Beijing, PR China. Electronic address: shenjingshan@simm.ac.cn.
PMID: 39504795 DOI: 10.1016/j.ejmech.2024.117004
Abstract

Given the high pathogenicity and rapid mutation rates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it is imperative to sustain efforts in drug research and development. Herein, we present the design, synthesis, and evaluation of peptidomimetic spiropyrrolidine derivatives as potent 3CLpro inhibitors against SARS-CoV-2. Among the synthesized derivatives, several compounds exhibited high potency in inhibiting 3CLpro, with IC50 values ranging from 21 nM to 53 nM. Notably, compounds 9b and 9h displayed improved enzymatic inhibition (IC50 = 25 nM and 21 nM, respectively) compared to nirmatrelvir (47 nM). Compound 9b showed enhanced stability in human and mouse liver microsomes compared to nirmatrelvir, whereas 9h exhibited similar stability to nirmatrelvir in both species. Furthermore, compound 9h displayed exceptional potency in cellular assays targeting the SARS-CoV-2 replicon within Huh7 cells, with a single-digit nanomolar activity that is 5.6 times better than that of nirmatrelvir. In a pharmacokinetic study in mice (PO, 20 mg/kg), compound 9h exhibited a prolonged plasma half-life (T1/2 = 2.58 h) compared to nirmatrelvir (T1/2 = 0.51 h) and demonstrated an AUC(0-t) value (1106 h∗ng/mL) equivalent to that of nirmatrelvir (1023 h∗ng/mL). These findings indicate that compound 9h is a promising lead for developing a novel 3CLpro inhibitor against SARS-CoV-2.

Keywords

3CL(pro) inhibitors; Peptidomimetics; SARS-CoV-2; Spiropyrrolidine derivatives.

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