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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 Mpro
Qi Yang 1 , Xupeng Huang 2 , Hongbo Zhang 3 , Jing Sun 4 , Jielin Tang 1 , Zhao Chen 4 , Lijie Liu 5 , Man Liu 6 , Zeyun Sun 5 , Zhenhao Tang 2 , Dandan Wei 2 , Dong Wang 4 , Yiliang Wang 7 , Mengrong Yan 2 , Li Zhao 5 , Airu Zhu 4 , Yihang Zhong 2 , Haitao Yang 8 , Yao Zhao 9 , Jun Dai 10 , Yongxia Shi 10 , Bo Huang 11 , Wei Zhang 12 , Jincun Zhao 13 , Xinwen Chen 14 , Zihe Rao 15 , Wei Peng 16
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 (Mpro) 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 Mpro. By fully exploring occupation of the S1, S2, and S3/S4 binding pockets, we identified eight promising inhibitors with half-maximal inhibitory concentration (IC50) values below 20 nM. The cocrystal structure of Mpro 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 Mpro. Compound 4 demonstrated outstanding in vitro antiviral activity against wild-type SARS-CoV-2 with an EC50 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 Mpro
Qi Yang 1 , Xupeng Huang 2 , Hongbo Zhang 3 , Jing Sun 4 , Jielin Tang 1 , Zhao Chen 4 , Lijie Liu 5 , Man Liu 6 , Zeyun Sun 5 , Zhenhao Tang 2 , Dandan Wei 2 , Dong Wang 4 , Yiliang Wang 7 , Mengrong Yan 2 , Li Zhao 5 , Airu Zhu 4 , Yihang Zhong 2 , Haitao Yang 8 , Yao Zhao 9 , Jun Dai 10 , Yongxia Shi 10 , Bo Huang 11 , Wei Zhang 12 , Jincun Zhao 13 , Xinwen Chen 14 , Zihe Rao 15 , Wei Peng 16
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 (Mpro) 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 Mpro. By fully exploring occupation of the S1, S2, and S3/S4 binding pockets, we identified eight promising inhibitors with half-maximal inhibitory concentration (IC50) values below 20 nM. The cocrystal structure of Mpro 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 Mpro. Compound 4 demonstrated outstanding in vitro antiviral activity against wild-type SARS-CoV-2 with an EC50 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.