Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease

Dai, Wenhao; Zhang, Bing; Jiang, Xia; Su, Haixia; Li, Jian; Zhao, Yao; Xie, Xizhou; Jin, Zhixing; Peng, Jingjing; Liu, Fengjiang; Li, Chunpu; You, Li; Bai, Fang; Wang, Haofeng; Cheng, Xi; Cen, Xiaobo; Hu, Shulei; Yang, Xiuna; Wang, Jiang; Liu, Xiang; Xiao, Gengfu; Jiang, Hualiang; Rao, Zihe; Zhang, Lei Ke; Xu, Yechun; Yang, Haitao; Liu, Hong

doi:10.1126/science.abb4489

Cited by 1,326 publications

(1,766 citation statements)

References 28 publications

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“…Recently, a related peptidyl inhibitor was reported with a similar warhead to our compound, but with an indole group at the P3 position and an IC 50 of 0.05±0.005 µM 16 . However, that compound has not been demonstrated to be efficacious in animals, as is the case for GC376.…”

Section: Gc373 and Gc376 Inhibit Sars-cov-2 M Promentioning

confidence: 63%

“…supernatants from cells untreated, and GC373 ( Figure 4C) or GC376 ( Figure 4D) treated cell cultures. It was observed that both GC373 and GC376 are potent inhibitors of SARS-CoV-2 decreasing viral titers 3 logs, compared with a 2 log decrease in recently published results using other aldehyde compounds 16 . These results indicate that both GC373 and GC376 are potent inhibitors of SARS-CoV-2 with a therapeutic index of >200.…”

Section: Gc373 and Gc376 Are Potent Inhibitors Of Sars-cov-2 In Cellmentioning

confidence: 69%

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Feline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication

Vuong

Khan

Fischer

et al. 2020

Preprint

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The COVID-19 pandemic, attributed to the SARS-CoV-2 coronavirus infection, resulted in millions infected worldwide and an immediate need for antiviral treatments. The main protease (M pro ) in SARS-CoV-2 is a viable drug target because of its essential role in the cleavage of the virus polypeptide and subsequent viral replication. Feline infectious peritonitis, a fatal infection in cats caused by a coronavirus, was successfully treated previously with a dipeptide-based protease inhibitor. Here we show this drug, GC376, and its analog GC373, are effective inhibitors of the M pro from both SARS-CoV and SARS-CoV-2 with IC 50 values in the nanomolar range. Crystal structures of the SARS-CoV and SARS-CoV-2 M pro with these inhibitors have a covalent modification of the nucleophilic Cys145. NMR analysis reveals that inhibition proceeds via reversible formation of a hemithioacetal. GC373 and GC376 are potent inhibitors of SARS-CoV-2 in cell culture, with EC 50 values near one micromolar and little to no toxicity. These protease inhibitors are soluble, non-toxic, and bind reversibly. They are strong drug candidates for the treatment of human coronavirus infections because they have already been successful in animals (cats). The work here lays the framework for their use in human trials for the treatment of COVID-19.was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 499.787 MHz H1 1D in cdcl3 (ref. to CDCl3 @ 7.26 ppm) temp 27.7 C -> actual temp = 27.0 C, colddual probe Sweep Width(Hz): 6009.62 Acquisiton Time(s): 5 Relaxation Delay(s): 0.1 Pulse Sequence: PRESAT Digital Res.(Hz/pt): 0.09 Hz per mm(Hz/mm): 25.04 Sweep Width(Hz): 6009.62 Acquisiton Time(s): 5 Relaxation Delay(s): 0.1 Pulse Sequence: PRESAT Digital Res.(Hz/pt): 0.09 Hz per mm(Hz/mm): 25.04 Sweep Width(Hz): 8389.26 Acquisiton Time(s): 5 Relaxation Delay(s): 0.1 Pulse Sequence: PRESAT Digital Res.(Hz/pt): 0.13 Hz per mm(Hz/mm): 34.95

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Section: Gc373 and Gc376 Inhibit Sars-cov-2 M Promentioning

confidence: 63%

Section: Gc373 and Gc376 Are Potent Inhibitors Of Sars-cov-2 In Cellmentioning

confidence: 69%

Feline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication

Vuong

Khan

Fischer

et al. 2020

Preprint

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“…The atomic level three-dimensional structure of several SARS-CoV-2 proteins have now been determined [10][11][12][13] . These X-ray crystallography based structures provide remarkable insights into macromolecular structure and intermolecular interactions.…”

Section: Introductionmentioning

confidence: 99%

Dynamics of the ACE2 - SARS-CoV/SARS-CoV-2 spike protein interface reveal unique mechanisms

Ali

Vijayan

2020

Preprint

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The coronavirus disease 2019 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a major public health concern. A handful of static structures now provide molecular insights into how SARS-CoV-2 and SARS-CoV interact with its host target, which is the angiotensin converting enzyme 2 (ACE2). Molecular recognition, binding and function are dynamic processes. To evaluate this, multiple all atom molecular dynamics simulations of at least 500 ns each were performed to better understand the structural stability and interfacial interactions between the receptor binding domain of the spike protein of SARS-CoV-2 and SARS-CoV bound to ACE2. Several contacts were observed to form, break and reform in the interface during the simulations. Our results indicate that SARS-CoV and SARS-CoV-2 utilizes unique strategies to achieve stable binding to ACE2. Several differences were observed between the residues of SARS-CoV-2 and SARS-CoV that consistently interacted with ACE2. Notably, a stable salt bridge between Lys417 of SARS-CoV-2 spike protein and Asp30 of ACE2 as well as three stable hydrogen bonds between Tyr449, Gln493, and Gln498 of SARS-CoV-2 and Asp38, Glu35, and Lys353 of ACE2 were observed, which were absent in the SARS-CoV-ACE2 interface. Some previously reported residues, which were suggested to enhance the binding affinity of SARS-CoV-2, were not observed to form stable interactions in these simulations. Stable binding to the host receptor is crucial for virus entry. Therefore, special consideration should be given to these stable interactions while designing potential drugs and treatment modalities to target or disrupt this interface.

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“…example therapeutics to show their approximate point of influence on the viral cycle(16,22,25,26). Examples are not exhaustive.…”

mentioning

confidence: 99%

Biophysical modeling of the SARS-CoV-2 viral cycle reveals ideal antiviral targets

Castle

Dock

Hemmat

et al. 2020

Preprint

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Effective therapies for COVID-19 are urgently needed. Presently there are more than 800 COVID-19 clinical trials globally, many with drug combinations, resulting in an empirical process with an enormous number of possible combinations. To identify the most promising potential therapies, we developed a biophysical model for the SARS-CoV-2 viral cycle and performed a sensitivity analysis for individual model parameters and all possible pairwise parameter changes (16 2 = 256 possibilities). We found that model-predicted virion production is fairly insensitive to changes in most viral entry, assembly, and release parameters, but highly sensitive to some viral transcription and translation parameters. Furthermore, we found a cooperative benefit to pairwise targeting of transcription and translation, predicting that combined targeting of these processes will be especially effective in inhibiting viral production.

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Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease

Cited by 1,326 publications

References 28 publications

Feline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication

Feline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication

Dynamics of the ACE2 - SARS-CoV/SARS-CoV-2 spike protein interface reveal unique mechanisms

Biophysical modeling of the SARS-CoV-2 viral cycle reveals ideal antiviral targets

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