tetano
Editor, Senior Moderator
Eur J Med Chem
. 2025 Mar 10:289:117497.
doi: 10.1016/j.ejmech.2025.117497. Online ahead of print. Expanding the utilization of binding pockets proves to be effective for noncovalent small molecule inhibitors against SARS-CoV-2 M[SUP]pro[/SUP]
Qi Yang[SUP] 1 [/SUP], Xupeng Huang[SUP] 2 [/SUP], Hongbo Zhang[SUP] 3 [/SUP], Jing Sun[SUP] 4 [/SUP], Jielin Tang[SUP] 1 [/SUP], Zhao Chen[SUP] 4 [/SUP], Lijie Liu[SUP] 5 [/SUP], Man Liu[SUP] 6 [/SUP], Zeyun Sun[SUP] 5 [/SUP], Zhenhao Tang[SUP] 2 [/SUP], Dandan Wei[SUP] 2 [/SUP], Dong Wang[SUP] 4 [/SUP], Yiliang Wang[SUP] 7 [/SUP], Mengrong Yan[SUP] 2 [/SUP], Li Zhao[SUP] 5 [/SUP], Airu Zhu[SUP] 4 [/SUP], Yihang Zhong[SUP] 2 [/SUP], Haitao Yang[SUP] 8 [/SUP], Yao Zhao[SUP] 9 [/SUP], Jun Dai[SUP] 10 [/SUP], Yongxia Shi[SUP] 10 [/SUP], Bo Huang[SUP] 11 [/SUP], Wei Zhang[SUP] 12 [/SUP], Jincun Zhao[SUP] 13 [/SUP], Xinwen Chen[SUP] 14 [/SUP], Zihe Rao[SUP] 15 [/SUP], Wei Peng[SUP] 16 [/SUP]
Affiliations
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths and continues to pose serious threats to global public health. The main protease (M[SUP]pro[/SUP]) of SARS-CoV-2 is crucial for viral replication and its conservation, making it an attractive drug target. Here, we employed a structure-based drug design strategy to develop and optimize novel inhibitors targeting SARS-CoV-2 M[SUP]pro[/SUP]. By fully exploring occupation of the S1, S2, and S3/S4 binding pockets, we identified eight promising inhibitors with half-maximal inhibitory concentration (IC[SUB]50[/SUB]) values below 20 nM. The cocrystal structure of M[SUP]pro[/SUP] with compound 10 highlighted the crucial roles of the interactions within the S3/S4 pockets in inhibitor potency enhancement. These findings demonstrated that expanding the utilization of these binding pockets was an effective strategy for developing noncovalent small molecule inhibitors that target SARS-CoV-2 M[SUP]pro[/SUP]. Compound 4 demonstrated outstanding in vitro antiviral activity against wild-type SARS-CoV-2 with an EC[SUB]50[/SUB] of 9.4 nM. Moreover, oral treatment with compounds 1 and 9 exhibited excellent antiviral potency and substantially ameliorated virus-induced tissue damage in the lungs of Omicron BA.5-infected K18-human ACE2 (K18-hACE2) transgenic mice, indicating that these novel noncovalent inhibitors could be potential oral agents for the treatment of COVID-19.
Keywords: In vivo antiviral activity; M(pro) inhibitors; Pharmacokinetics properties; SARS-CoV-2.
. 2025 Mar 10:289:117497.
doi: 10.1016/j.ejmech.2025.117497. Online ahead of print. Expanding the utilization of binding pockets proves to be effective for noncovalent small molecule inhibitors against SARS-CoV-2 M[SUP]pro[/SUP]
Qi Yang[SUP] 1 [/SUP], Xupeng Huang[SUP] 2 [/SUP], Hongbo Zhang[SUP] 3 [/SUP], Jing Sun[SUP] 4 [/SUP], Jielin Tang[SUP] 1 [/SUP], Zhao Chen[SUP] 4 [/SUP], Lijie Liu[SUP] 5 [/SUP], Man Liu[SUP] 6 [/SUP], Zeyun Sun[SUP] 5 [/SUP], Zhenhao Tang[SUP] 2 [/SUP], Dandan Wei[SUP] 2 [/SUP], Dong Wang[SUP] 4 [/SUP], Yiliang Wang[SUP] 7 [/SUP], Mengrong Yan[SUP] 2 [/SUP], Li Zhao[SUP] 5 [/SUP], Airu Zhu[SUP] 4 [/SUP], Yihang Zhong[SUP] 2 [/SUP], Haitao Yang[SUP] 8 [/SUP], Yao Zhao[SUP] 9 [/SUP], Jun Dai[SUP] 10 [/SUP], Yongxia Shi[SUP] 10 [/SUP], Bo Huang[SUP] 11 [/SUP], Wei Zhang[SUP] 12 [/SUP], Jincun Zhao[SUP] 13 [/SUP], Xinwen Chen[SUP] 14 [/SUP], Zihe Rao[SUP] 15 [/SUP], Wei Peng[SUP] 16 [/SUP]
Affiliations
- PMID: 40090296
- DOI: 10.1016/j.ejmech.2025.117497
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths and continues to pose serious threats to global public health. The main protease (M[SUP]pro[/SUP]) of SARS-CoV-2 is crucial for viral replication and its conservation, making it an attractive drug target. Here, we employed a structure-based drug design strategy to develop and optimize novel inhibitors targeting SARS-CoV-2 M[SUP]pro[/SUP]. By fully exploring occupation of the S1, S2, and S3/S4 binding pockets, we identified eight promising inhibitors with half-maximal inhibitory concentration (IC[SUB]50[/SUB]) values below 20 nM. The cocrystal structure of M[SUP]pro[/SUP] with compound 10 highlighted the crucial roles of the interactions within the S3/S4 pockets in inhibitor potency enhancement. These findings demonstrated that expanding the utilization of these binding pockets was an effective strategy for developing noncovalent small molecule inhibitors that target SARS-CoV-2 M[SUP]pro[/SUP]. Compound 4 demonstrated outstanding in vitro antiviral activity against wild-type SARS-CoV-2 with an EC[SUB]50[/SUB] of 9.4 nM. Moreover, oral treatment with compounds 1 and 9 exhibited excellent antiviral potency and substantially ameliorated virus-induced tissue damage in the lungs of Omicron BA.5-infected K18-human ACE2 (K18-hACE2) transgenic mice, indicating that these novel noncovalent inhibitors could be potential oral agents for the treatment of COVID-19.
Keywords: In vivo antiviral activity; M(pro) inhibitors; Pharmacokinetics properties; SARS-CoV-2.