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Article ; Online: Ebselen, Disulfiram, Carmofur, PX-12, Tideglusib, and Shikonin Are Nonspecific Promiscuous SARS-CoV-2 Main Protease Inhibitors.

Ma, Chunlong / Hu, Yanmei / Townsend, Julia Alma / Lagarias, Panagiotis I / Marty, Michael Thomas / Kolocouris, Antonios / Wang, Jun

ACS pharmacology & translational science

2020 Volume 3, Issue 6, Page(s) 1265–1277

Abstract: Among the drug targets being investigated for SARS-CoV-2, the viral main protease ( ... ...

Abstract	Among the drug targets being investigated for SARS-CoV-2, the viral main protease (M
Language	English
Publishing date	2020-10-09
Publishing country	United States
Document type	Journal Article
ISSN	2575-9108
ISSN (online)	2575-9108
DOI	10.1021/acsptsci.0c00130
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Ebselen, disulfiram, carmofur, PX-12, tideglusib, and shikonin are non-specific promiscuous SARS-CoV-2 main protease inhibitors.

Ma, Chunlong / Hu, Yanmei / Townsend, Julia Alma / Lagarias, Panagiotis I / Marty, Michael Thomas / Kolocouris, Antonios / Wang, Jun

bioRxiv : the preprint server for biology

2020

Abstract: There is an urgent need for vaccines and antiviral drugs to combat the COVID-19 pandemic. Encouraging progress has been made in developing antivirals targeting SARS-CoV-2, the etiological agent of COVID-19. Among the drug targets being investigated, the ... ...

Abstract	There is an urgent need for vaccines and antiviral drugs to combat the COVID-19 pandemic. Encouraging progress has been made in developing antivirals targeting SARS-CoV-2, the etiological agent of COVID-19. Among the drug targets being investigated, the viral main protease (M
Keywords	covid19
Language	English
Publishing date	2020-09-16
Publishing country	United States
Document type	Preprint
DOI	10.1101/2020.09.15.299164
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Discovery of SARS-CoV-2 papain-like protease inhibitors through a combination of high-throughput screening and FlipGFP-based reporter assay.

Xia, Zilei / Sacco, Michael Dominic / Ma, Chunlong / Townsend, Julia Alma / Kitamura, Naoya / Hu, Yanmei / Ba, Mandy / Szeto, Tommy / Zhang, Xiujun / Meng, Xiangzhi / Zhang, Fushun / Xiang, Yan / Marty, Michael Thomas / Chen, Yu / Wang, Jun

bioRxiv : the preprint server for biology

2021

Abstract: The papain-like protease ( ... ...

Abstract	The papain-like protease (PL
Language	English
Publishing date	2021-03-16
Publishing country	United States
Document type	Preprint
DOI	10.1101/2021.03.15.435551
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Discovery of Di- and Trihaloacetamides as Covalent SARS-CoV-2 Main Protease Inhibitors with High Target Specificity

Ma, Chunlong / Xia, Zilei / Sacco, Michael Dominic / Hu, Yanmei / Townsend, Julia Alma / Meng, Xiangzhi / Choza, Juliana / Tan, Haozhou / Jang, Janice / Gongora, Maura V. / Zhang, Xiujun / Zhang, Fushun / Xiang, Yan / Marty, Michael Thomas / Chen, Yu / Wang, Jun

Journal of the American Chemical Society. 2021 Dec. 03, v. 143, no. 49

2021

Abstract: The main protease (Mᵖʳᵒ) is a validated antiviral drug target of SARS-CoV-2. A number of Mᵖʳᵒ inhibitors have now advanced to animal model study and human clinical trials. However, one issue yet to be addressed is the target selectivity over host ... ...

Abstract	The main protease (Mᵖʳᵒ) is a validated antiviral drug target of SARS-CoV-2. A number of Mᵖʳᵒ inhibitors have now advanced to animal model study and human clinical trials. However, one issue yet to be addressed is the target selectivity over host proteases such as cathepsin L. In this study we describe the rational design of covalent SARS-CoV-2 Mᵖʳᵒ inhibitors with novel cysteine reactive warheads including dichloroacetamide, dibromoacetamide, tribromoacetamide, 2-bromo-2,2-dichloroacetamide, and 2-chloro-2,2-dibromoacetamide. The promising lead candidates Jun9-62-2R (dichloroacetamide) and Jun9-88-6R (tribromoacetamide) had not only potent enzymatic inhibition and antiviral activity but also significantly improved target specificity over caplain and cathepsins. Compared to GC-376, these new compounds did not inhibit the host cysteine proteases including calpain I, cathepsin B, cathepsin K, cathepsin L, and caspase-3. To the best of our knowledge, they are among the most selective covalent Mᵖʳᵒ inhibitors reported thus far. The cocrystal structures of SARS-CoV-2 Mᵖʳᵒ with Jun9-62-2R and Jun9-57-3R reaffirmed our design hypothesis, showing that both compounds form a covalent adduct with the catalytic C145. Overall, these novel compounds represent valuable chemical probes for target validation and drug candidates for further development as SARS-CoV-2 antivirals.
Keywords	Severe acute respiratory syndrome coronavirus 2 ; animal models ; antiviral agents ; antiviral properties ; calpain ; caspase-3 ; cathepsin B ; cathepsin K ; cathepsin L ; cysteine ; enzyme inhibition ; humans
Language	English
Dates of publication	2021-1203
Size	p. 20697-20709.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/jacs.1c08060
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV-2 viral replication by targeting the viral main protease.

Ma, Chunlong / Sacco, Michael Dominic / Hurst, Brett / Townsend, Julia Alma / Hu, Yanmei / Szeto, Tommy / Zhang, Xiujun / Tarbet, Bart / Marty, Michael Thomas / Chen, Yu / Wang, Jun

Cell research

2020 Volume 30, Issue 8, Page(s) 678–692

Abstract: A new coronavirus SARS-CoV-2, also called novel coronavirus 2019 (2019-nCoV), started to circulate among humans around December 2019, and it is now widespread as a global pandemic. The disease caused by SARS-CoV-2 virus is called COVID-19, which is ... ...

Abstract	A new coronavirus SARS-CoV-2, also called novel coronavirus 2019 (2019-nCoV), started to circulate among humans around December 2019, and it is now widespread as a global pandemic. The disease caused by SARS-CoV-2 virus is called COVID-19, which is highly contagious and has an overall mortality rate of 6.35% as of May 26, 2020. There is no vaccine or antiviral available for SARS-CoV-2. In this study, we report our discovery of inhibitors targeting the SARS-CoV-2 main protease (M
MeSH term(s)	A549 Cells ; Animals ; Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; Betacoronavirus/enzymology ; COVID-19 ; Caco-2 Cells ; Chlorocebus aethiops ; Coronavirus 3C Proteases ; Coronavirus Infections/metabolism ; Coronavirus Infections/virology ; Cysteine Endopeptidases/chemistry ; Cysteine Endopeptidases/metabolism ; Drug Discovery/methods ; Glycoproteins/pharmacology ; Humans ; Inhibitory Concentration 50 ; Kinetics ; Pandemics ; Pneumonia, Viral/metabolism ; Pneumonia, Viral/virology ; Proline/analogs & derivatives ; Proline/pharmacology ; Protein Conformation ; Pyrrolidines/chemistry ; Pyrrolidines/pharmacology ; SARS-CoV-2 ; Sulfonic Acids ; Vero Cells ; Viral Nonstructural Proteins/antagonists & inhibitors ; Viral Nonstructural Proteins/chemistry ; Viral Nonstructural Proteins/metabolism ; Virus Replication/drug effects
Chemical Substances	Antiviral Agents ; Glycoproteins ; Pyrrolidines ; Sulfonic Acids ; Viral Nonstructural Proteins ; calpain inhibitors ; N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide (89BT58KELH) ; Proline (9DLQ4CIU6V) ; Cysteine Endopeptidases (EC 3.4.22.-) ; Coronavirus 3C Proteases (EC 3.4.22.28) ; GC376 (H1NMJ5XDG5)
Keywords	covid19
Language	English
Publishing date	2020-06-15
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1319303-x
ISSN	1748-7838 ; 1001-0602
ISSN (online)	1748-7838
ISSN	1001-0602
DOI	10.1038/s41422-020-0356-z
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Discovery of SARS-CoV-2 Papain-like Protease Inhibitors through a Combination of High-Throughput Screening and a FlipGFP-Based Reporter Assay.

Ma, Chunlong / Sacco, Michael Dominic / Xia, Zilei / Lambrinidis, George / Townsend, Julia Alma / Hu, Yanmei / Meng, Xiangzhi / Szeto, Tommy / Ba, Mandy / Zhang, Xiujun / Gongora, Maura / Zhang, Fushun / Marty, Michael Thomas / Xiang, Yan / Kolocouris, Antonios / Chen, Yu / Wang, Jun

ACS central science

2021 Volume 7, Issue 7, Page(s) 1245–1260

Abstract: The papain-like protease ( ... ...

Abstract	The papain-like protease (PL
Language	English
Publishing date	2021-06-18
Publishing country	United States
Document type	Journal Article
ISSN	2374-7943
ISSN	2374-7943
DOI	10.1021/acscentsci.1c00519
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Discovery of Di- and Trihaloacetamides as Covalent SARS-CoV-2 Main Protease Inhibitors with High Target Specificity.

Ma, Chunlong / Xia, Zilei / Sacco, Michael Dominic / Hu, Yanmei / Townsend, Julia Alma / Meng, Xiangzhi / Choza, Juliana / Tan, Haozhou / Jang, Janice / Gongora, Maura V / Zhang, Xiujun / Zhang, Fushun / Xiang, Yan / Marty, Michael Thomas / Chen, Yu / Wang, Jun

Journal of the American Chemical Society

2021 Volume 143, Issue 49, Page(s) 20697–20709

Abstract: The main protease ( ... ...

Abstract	The main protease (M
MeSH term(s)	Acetamides/pharmacology ; Animals ; Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; Cathepsin L/antagonists & inhibitors ; Coronavirus 3C Proteases/antagonists & inhibitors ; Drug Design ; Drug Discovery ; Enzyme Inhibitors/pharmacology ; Humans ; Models, Molecular ; Molecular Dynamics Simulation ; Protease Inhibitors/pharmacology ; SARS-CoV-2/drug effects ; Structure-Activity Relationship ; Substrate Specificity
Chemical Substances	Acetamides ; Antiviral Agents ; Enzyme Inhibitors ; Protease Inhibitors ; 3C-like proteinase, SARS-CoV-2 (EC 3.4.22.-) ; Cathepsin L (EC 3.4.22.15) ; Coronavirus 3C Proteases (EC 3.4.22.28)
Language	English
Publishing date	2021-12-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3155-0
ISSN	1520-5126 ; 0002-7863
ISSN (online)	1520-5126
ISSN	0002-7863
DOI	10.1021/jacs.1c08060
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Expedited Approach toward the Rational Design of Noncovalent SARS-CoV-2 Main Protease Inhibitors.

Kitamura, Naoya / Sacco, Michael Dominic / Ma, Chunlong / Hu, Yanmei / Townsend, Julia Alma / Meng, Xiangzhi / Zhang, Fushun / Zhang, Xiujun / Ba, Mandy / Szeto, Tommy / Kukuljac, Adis / Marty, Michael Thomas / Schultz, David / Cherry, Sara / Xiang, Yan / Chen, Yu / Wang, Jun

Journal of medicinal chemistry

2021 Volume 65, Issue 4, Page(s) 2848–2865

Abstract: The main protease ( ... ...

Abstract	The main protease (M
MeSH term(s)	Animals ; Antiviral Agents/chemical synthesis ; Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; COVID-19/metabolism ; Chlorocebus aethiops ; Coronavirus 3C Proteases/antagonists & inhibitors ; Coronavirus 3C Proteases/isolation & purification ; Coronavirus 3C Proteases/metabolism ; Cysteine Proteinase Inhibitors/chemical synthesis ; Cysteine Proteinase Inhibitors/chemistry ; Cysteine Proteinase Inhibitors/pharmacology ; Dose-Response Relationship, Drug ; Drug Design ; Humans ; Microbial Sensitivity Tests ; Models, Molecular ; Molecular Structure ; Proline/analogs & derivatives ; Proline/chemical synthesis ; Proline/chemistry ; Proline/pharmacology ; Pyrrolidines/chemical synthesis ; Pyrrolidines/chemistry ; Pyrrolidines/pharmacology ; SARS-CoV-2/drug effects ; SARS-CoV-2/enzymology ; Sulfonic Acids/chemical synthesis ; Sulfonic Acids/chemistry ; Sulfonic Acids/pharmacology ; Vero Cells ; COVID-19 Drug Treatment
Chemical Substances	Antiviral Agents ; Cysteine Proteinase Inhibitors ; Pyrrolidines ; Sulfonic Acids ; N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide (89BT58KELH) ; Proline (9DLQ4CIU6V) ; 3C-like proteinase, SARS-CoV-2 (EC 3.4.22.-) ; Coronavirus 3C Proteases (EC 3.4.22.28) ; GC376 (H1NMJ5XDG5)
Language	English
Publishing date	2021-04-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.1c00509
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Ebselen, disulfiram, carmofur, PX-12, tideglusib, and shikonin are non-specific promiscuous SARS-CoV-2 main protease inhibitors

Ma, Chunlong / Hu, Yanmei / Townsend, Julia Alma / Lagarias, Panagiotis / Marty, Michael Thomas / Kolocouris, Antonios / Wang, Jun

bioRxiv

Abstract	There is an urgent need for vaccines and antiviral drugs to combat the COVID-19 pandemic. Encouraging progress has been made in developing antivirals targeting SARS-CoV-2, the etiological agent of COVID-19. Among the drug targets being investigated, the viral main protease (Mpro) is one of the most extensively studied drug targets. Mpro is a cysteine protease that hydrolyzes the viral polyprotein at more than 11 sites and it is highly conserved among coronaviruses. In addition, Mpro has a unique substrate preference for glutamine in the P1 position. Taken together, it appears that Mpro inhibitors can achieve both broad-spectrum antiviral activity and a high selectivity index. Structurally diverse compounds have been reported as Mpro inhibitors, with several of which also showed antiviral activity in cell culture. In this study, we investigated the mechanism of action of six previously reported Mpro inhibitors, ebselen, disulfiram, tideglusib, carmofur, shikonin, and PX-12 using a consortium of techniques including FRET-based enzymatic assay, thermal shift assay, native mass spectrometry, cellular antiviral assays, and molecular dynamics simulations. Collectively, the results showed that the inhibition of Mpro by these six compounds is non-specific and the inhibition is abolished or greatly reduced with the addition of reducing reagent DTT. In the absence of DTT, these six compounds not only inhibit Mpro, but also a panel of viral cysteine proteases including SARS-CoV-2 papain-like protease, the 2Apro and 3Cpro from enterovirus A71 (EV-A71) and EV-D68. However, none of the compounds inhibits the viral replication of EV-A71 or EV-D68, suggesting that the enzymatic inhibition potency IC50 values obtained in the absence of DTT cannot be used to faithfully predict their cellular antiviral activity. Overall, we provide compelling evidence suggesting that ebselen, disulfiram, tideglusib, carmofur, shikonin, and PX-12 are non-specific SARS-CoV-2 Mpro inhibitors, and urge the scientific community to be stringent with hit validation.
Keywords	covid19
Language	English
Publishing date	2020-09-16
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2020.09.15.299164
Database	COVID19

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Article: Ebselen, Disulfiram, Carmofur, PX-12, Tideglusib, and Shikonin Are Nonspecific Promiscuous SARS-CoV-2 Main Protease Inhibitors

Ma, Chunlong / Hu, Yanmei / Townsend, Julia Alma / Lagarias, Panagiotis I. / Marty, Michael Thomas / Kolocouris, Antonios / Wang, Jun

ACS Pharmacology & Translational Science

Abstract: Among the drug targets being investigated for SARS-CoV-2, the viral main protease (Mpro) is one of the most extensively studied Mpro is a cysteine protease that hydrolyzes the viral polyprotein at more than 11 sites It is highly conserved and has a ... ...

Abstract	Among the drug targets being investigated for SARS-CoV-2, the viral main protease (Mpro) is one of the most extensively studied Mpro is a cysteine protease that hydrolyzes the viral polyprotein at more than 11 sites It is highly conserved and has a unique substrate preference for glutamine in the P1 position Therefore, Mpro inhibitors are expected to have broad-spectrum antiviral activity and a high selectivity index Structurally diverse compounds have been reported as Mpro inhibitors In this study, we investigated the mechanism of action of six previously reported Mpro inhibitors, ebselen, disulfiram, tideglusib, carmofur, shikonin, and PX-12, using a consortium of techniques including FRET-based enzymatic assay, thermal shift assay, native mass spectrometry, cellular antiviral assays, and molecular dynamics simulations Collectively, the results showed that the inhibition of Mpro by these six compounds is nonspecific and that the inhibition is abolished or greatly reduced with the addition of reducing reagent 1,4-dithiothreitol (DTT) Without DTT, these six compounds inhibit not only Mpro but also a panel of viral cysteine proteases including SARS-CoV-2 papain-like protease and 2Apro and 3Cpro from enterovirus A71 (EV-A71) and EV-D68 However, none of the compounds inhibits the viral replication of EV-A71 or EV-D68, suggesting that the enzymatic inhibition potency IC50 values obtained in the absence of DTT cannot be used to faithfully predict their cellular antiviral activity Overall, we provide compelling evidence suggesting that these six compounds are nonspecific SARS-CoV-2 Mpro inhibitors and urge the scientific community to be stringent with hit validation
Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #840621
Database	COVID19

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