Design, Synthesis, and Biological Evaluation of Peptidomimetic Aldehydes as Broad-Spectrum Inhibitors against Enterovirus and SARS-CoV-2

Wenhao Dai; Dirk Jochmans; Hang Xie; Hang Yang; Jian Li; Haixia Su; Di Chang; Jiang Wang; Jingjing Peng; Lili Zhu; Yong Nian; Rolf Hilgenfeld; Hualiang Jiang; Kaixian Chen; Leike Zhang; Yechun Xu; Johan Neyts; Hong Liu

doi:10.1021/acs.jmedchem.0c02258

Design, Synthesis, and Biological Evaluation of Peptidomimetic Aldehydes as Broad-Spectrum Inhibitors against Enterovirus and SARS-CoV-2

Wenhao Dai, Dirk Jochmans, Hang Xie, Hang Yang, Jian Li, Haixia Su, Di Chang, Jiang Wang, Jingjing Peng, Lili Zhu, Yong Nian, Rolf Hilgenfeld, Hualiang Jiang, Kaixian Chen, Leike Zhang, Yechun Xu, Johan Neyts, Hong Liu

Abstract

A novel series of peptidomimetic aldehydes was designed and synthesized to target 3C protease (3Cpro) of enterovirus 71 (EV71). Most of the compounds exhibited high antiviral activity, and among them, compound 18p demonstrated potent enzyme inhibitory activity and broad-spectrum antiviral activity on a panel of enteroviruses and rhinoviruses. The crystal structure of EV71 3Cpro in complex with 18p determined at a resolution of 1.2 Å revealed that 18p covalently linked to the catalytic Cys147 with an aldehyde group. In addition, these compounds also exhibited good inhibitory activity against the 3CLpro and the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), especially compound 18p (IC50 = 0.034 μM, EC50 = 0.29 μM). According to our previous work, these compounds have no reasons for concern regarding acute toxicity. Compared with AG7088, compound 18p also exhibited good pharmacokinetic properties and more potent anticoronavirus activity, making it an excellent lead for further development.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	65
Issue number	4
Pages (from-to)	2794-2808
Number of pages	15
ISSN	0223-5234
DOIs	https://doi.org/10.1021/acs.jmedchem.0c02258
Publication status	Published - 24.02.2022

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Research on SARS-CoV-2 / COVID-19

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10.1021/acs.jmedchem.0c02258

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Dai, W., Jochmans, D., Xie, H., Yang, H., Li, J., Su, H., Chang, D., Wang, J., Peng, J., Zhu, L., Nian, Y., Hilgenfeld, R., Jiang, H., Chen, K., Zhang, L., Xu, Y., Neyts, J., & Liu, H. (2022). Design, Synthesis, and Biological Evaluation of Peptidomimetic Aldehydes as Broad-Spectrum Inhibitors against Enterovirus and SARS-CoV-2. Journal of Medicinal Chemistry, 65(4), 2794-2808. https://doi.org/10.1021/acs.jmedchem.0c02258

@article{2057da2fdc2d434f8865cfa37b87b7b0,

title = "Design, Synthesis, and Biological Evaluation of Peptidomimetic Aldehydes as Broad-Spectrum Inhibitors against Enterovirus and SARS-CoV-2",

abstract = "A novel series of peptidomimetic aldehydes was designed and synthesized to target 3C protease (3Cpro) of enterovirus 71 (EV71). Most of the compounds exhibited high antiviral activity, and among them, compound 18p demonstrated potent enzyme inhibitory activity and broad-spectrum antiviral activity on a panel of enteroviruses and rhinoviruses. The crystal structure of EV71 3Cpro in complex with 18p determined at a resolution of 1.2 {\AA} revealed that 18p covalently linked to the catalytic Cys147 with an aldehyde group. In addition, these compounds also exhibited good inhibitory activity against the 3CLpro and the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), especially compound 18p (IC50 = 0.034 μM, EC50 = 0.29 μM). According to our previous work, these compounds have no reasons for concern regarding acute toxicity. Compared with AG7088, compound 18p also exhibited good pharmacokinetic properties and more potent anticoronavirus activity, making it an excellent lead for further development.",

author = "Wenhao Dai and Dirk Jochmans and Hang Xie and Hang Yang and Jian Li and Haixia Su and Di Chang and Jiang Wang and Jingjing Peng and Lili Zhu and Yong Nian and Rolf Hilgenfeld and Hualiang Jiang and Kaixian Chen and Leike Zhang and Yechun Xu and Johan Neyts and Hong Liu",

note = "Publisher Copyright: {\textcopyright} 2021 American Chemical Society.",

year = "2022",

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day = "24",

doi = "10.1021/acs.jmedchem.0c02258",

language = "English",

volume = "65",

pages = "2794--2808",

journal = "Journal of Medicinal Chemistry",

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Dai, W, Jochmans, D, Xie, H, Yang, H, Li, J, Su, H, Chang, D, Wang, J, Peng, J, Zhu, L, Nian, Y, Hilgenfeld, R, Jiang, H, Chen, K, Zhang, L, Xu, Y, Neyts, J & Liu, H 2022, 'Design, Synthesis, and Biological Evaluation of Peptidomimetic Aldehydes as Broad-Spectrum Inhibitors against Enterovirus and SARS-CoV-2', Journal of Medicinal Chemistry, vol. 65, no. 4, pp. 2794-2808. https://doi.org/10.1021/acs.jmedchem.0c02258

TY - JOUR

T1 - Design, Synthesis, and Biological Evaluation of Peptidomimetic Aldehydes as Broad-Spectrum Inhibitors against Enterovirus and SARS-CoV-2

AU - Dai, Wenhao

AU - Jochmans, Dirk

AU - Xie, Hang

AU - Yang, Hang

AU - Li, Jian

AU - Su, Haixia

AU - Chang, Di

AU - Wang, Jiang

AU - Peng, Jingjing

AU - Zhu, Lili

AU - Nian, Yong

AU - Hilgenfeld, Rolf

AU - Jiang, Hualiang

AU - Chen, Kaixian

AU - Zhang, Leike

AU - Xu, Yechun

AU - Neyts, Johan

AU - Liu, Hong

PY - 2022/2/24

Y1 - 2022/2/24

N2 - A novel series of peptidomimetic aldehydes was designed and synthesized to target 3C protease (3Cpro) of enterovirus 71 (EV71). Most of the compounds exhibited high antiviral activity, and among them, compound 18p demonstrated potent enzyme inhibitory activity and broad-spectrum antiviral activity on a panel of enteroviruses and rhinoviruses. The crystal structure of EV71 3Cpro in complex with 18p determined at a resolution of 1.2 Å revealed that 18p covalently linked to the catalytic Cys147 with an aldehyde group. In addition, these compounds also exhibited good inhibitory activity against the 3CLpro and the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), especially compound 18p (IC50 = 0.034 μM, EC50 = 0.29 μM). According to our previous work, these compounds have no reasons for concern regarding acute toxicity. Compared with AG7088, compound 18p also exhibited good pharmacokinetic properties and more potent anticoronavirus activity, making it an excellent lead for further development.

AB - A novel series of peptidomimetic aldehydes was designed and synthesized to target 3C protease (3Cpro) of enterovirus 71 (EV71). Most of the compounds exhibited high antiviral activity, and among them, compound 18p demonstrated potent enzyme inhibitory activity and broad-spectrum antiviral activity on a panel of enteroviruses and rhinoviruses. The crystal structure of EV71 3Cpro in complex with 18p determined at a resolution of 1.2 Å revealed that 18p covalently linked to the catalytic Cys147 with an aldehyde group. In addition, these compounds also exhibited good inhibitory activity against the 3CLpro and the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), especially compound 18p (IC50 = 0.034 μM, EC50 = 0.29 μM). According to our previous work, these compounds have no reasons for concern regarding acute toxicity. Compared with AG7088, compound 18p also exhibited good pharmacokinetic properties and more potent anticoronavirus activity, making it an excellent lead for further development.

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U2 - 10.1021/acs.jmedchem.0c02258

DO - 10.1021/acs.jmedchem.0c02258

M3 - Journal articles

C2 - 33872498

SN - 0223-5234

VL - 65

SP - 2794

EP - 2808

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 4

ER -

Design, Synthesis, and Biological Evaluation of Peptidomimetic Aldehydes as Broad-Spectrum Inhibitors against Enterovirus and SARS-CoV-2

Abstract

Coronavirus related work

UN SDGs

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