Crystal structure of SARS-CoV-2 main protease in complex with the natural product inhibitor shikonin illuminates a unique binding mode

Li, Jian; Zhou, Xuelan; Zhang, Yan; Zhong, Fanglin; Lin, Cheng Wen; McCormick, Peter J.; Jiang, Feng; Luo, Jun; Zhou, Huan; Wang, Qisheng; Fu, Yang; Duan, Jingjing; Zhang, Jin

doi:10.1016/j.scib.2020.10.018

Cited by 54 publications

(53 citation statements)

References 10 publications

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“…Among the known M pro inhibitors, the majority of them are covalent inhibitors such as GC376 analogs that contain a pyrollidone in the P1 position as a glutamine mimetic. Several structurally distinct compounds including ebselen, disulfiram, carmofur, PX-12, tideglusib, and shiknonin were claimed as M pro inhibitors 16,17 , but were later invalidated as promiscuous non-specific cysteine protease inhibitors 18,19 . In addition, non-covalent inhibitors such as ML188 (R) were developed and validated as SARS-CoV M pro inhibitors 5,12 .…”

Section: Discussionmentioning

confidence: 99%

“…2c).Consistent with the design hypothesis, several compounds including 14, 17, 18, 19, 20, 21, and 23 had significantly improved enzymatic inhibition (IC 50 < 3 µM) compared to compound 13.Replacing the tert-butyl in compound 13 with the bulkier trimethylsilyl led to compound 14 with a 2.9-fold increase in M pro inhibition. Cyclohexyl(17), thienyl (19), pyrrolyl(20), pyridinyl(21), and phenyl(23) were found to be the most favorable substitutions at the S2 pocket. Compound 16 with piperidyl substitution had similar potency as compound 13, while compound 15 with O-tert butyl was less active.…”

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confidence: 94%

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An expedited approach towards the rationale design of non-covalent SARS-CoV-2 main protease inhibitors with in vitro antiviral activity

Kitamura

Sacco

et al. 2020

Preprint

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The main protease (Mpro) of SARS-CoV-2 is a validated antiviral drug target. Several Mpro inhibitors have been reported with potent enzymatic inhibition and cellular antiviral activity, including GC376, boceprevir, calpain inhibitors II and XII, each containing a reactive warhead that covalently modifies the catalytic Cys145. In this study, we report an expedited drug discovery approach by coupling structure-based design and Ugi four-component (Ugi-4CR) reaction methodology to the design of non-covalent Mpro inhibitors. The most potent compound 23R had cellular antiviral activity similar to covalent inhibitors such as GC376. Our designs were guided by overlaying the structure of SARS-CoV Mpro + ML188 (R), a non-covalent inhibitor derived from Ug-4CR, with the X-ray crystal structures of SARS-CoV-2 Mpro + calpain inhibitor XII/GC376/UAWJ247. Binding site analysis suggests a strategy of extending the P2 and P3 substitutions in ML188 (R) to achieve optimal shape complementary with SARS-CoV-2 Mpro. Lead optimization led to the discovery of 23R, which inhibits SARS-CoV-2 Mpro and SARS-CoV-2 viral replication with an IC50 of 0.31 μM and EC50 of 1.27 μM, respectively. The binding and specificity of 23R to SARS-CoV-2 Mpro were confirmed in a thermal shift assay and native mass spectrometry assay. The co-crystal structure of SARS-CoV-2 Mpro with 23R revealed the P2 biphenyl fits snuggly into the S2 pocket and the benzyl group in the α-methylbenzyl faces towards the core of the enzyme, occupying a previously unexplored binding site located in between the S2 and S4 pockets. Overall, this study revealed the most potent non-covalent SARS-CoV-2 Mpro inhibitors reported to date and a novel binding pocket that can be explored for Mpro inhibitor design.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 94%

An expedited approach towards the rationale design of non-covalent SARS-CoV-2 main protease inhibitors with in vitro antiviral activity

Kitamura

Sacco

et al. 2020

Preprint

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“…3 A and B) and generated various different views of the overall structure of SARS-CoV-2 M pro in complex with shikonin ( Fig. 3 C) ( Li et al, 2020a ). Li et al demonstrated that the catalytic dyad His41 and Cys145 residues undergo huge conformational changes, creating a striking difference with other reported structures ( Dai et al, 2020 ; Zhang et al, 2020e ).…”

Section: Promising Active Ingredients Of Chinese Herbal Medicine Thatmentioning

confidence: 99%

“…Li et al demonstrated that the catalytic dyad His41 and Cys145 residues undergo huge conformational changes, creating a striking difference with other reported structures ( Dai et al, 2020 ; Zhang et al, 2020e ). Further analysis of the shikonin binding pocket revealed three novel interactions (π-π interactions with the His41 residue, hydrogen bond interactions with the Gln189 and Thr190 residues, and hydrogen bond interactions with the Met165, His164, and Cys145 residues) ( Li et al, 2020a ). This study demonstrated different binding patterns, thus suggesting significant diversity in terms of binding sites.…”

Section: Promising Active Ingredients Of Chinese Herbal Medicine Thatmentioning

confidence: 99%

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Chinese herbal medicine: Fighting SARS-CoV-2 infection on all fronts

Wang

Yang

2021

Journal of Ethnopharmacology

123

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The direct and indirect effects of bioactive compounds against coronavirus

et al. 2021

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Emerging viruses are known to pose a threat to humans in the world. COVID‐19, a newly emerging viral respiratory disease, can spread quickly from people to people via respiratory droplets, cough, sneeze, or exhale. Up to now, there are no specific therapies found for the treatment of COVID‐19. In this sense, the rising demand for effective antiviral drugs is stressed. The main goal of the present study is to cover the current literature about bioactive compounds (e.g., polyphenols, glucosinolates, carotenoids, minerals, vitamins, oligosaccharides, bioactive peptides, essential oils, and probiotics) with potential efficiency against COVID‐19, showing antiviral activities via the inhibition of coronavirus entry into the host cell, coronavirus enzymes, as well as the virus replication in human cells. In turn, these compounds can boost the immune system, helping fight against COVID‐19. Overall, it can be concluded that bioactives and the functional foods containing these compounds can be natural alternatives for boosting the immune system and defeating coronavirus.

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Crystal structure of SARS-CoV-2 main protease in complex with the natural product inhibitor shikonin illuminates a unique binding mode

Abstract: Graphical abstract

Cited by 54 publications

References 10 publications

An expedited approach towards the rationale design of non-covalent SARS-CoV-2 main protease inhibitors with in vitro antiviral activity

An expedited approach towards the rationale design of non-covalent SARS-CoV-2 main protease inhibitors with in vitro antiviral activity

Chinese herbal medicine: Fighting SARS-CoV-2 infection on all fronts

The direct and indirect effects of bioactive compounds against coronavirus

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