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Article ; Online: Covalent Inactivation of

Pham, Truc Viet / Mellott, Drake M / Moghadamchargari, Zahra / Chen, Kevin / Krieger, Inna / Laganowsky, Arthur / Sacchettini, James C / Meek, Thomas D

ACS chemical biology

2021 Volume 16, Issue 3, Page(s) 463–470

Abstract: The isocitrate lyases (ICL1/2) are essential enzymes ... ...

Abstract	The isocitrate lyases (ICL1/2) are essential enzymes of
MeSH term(s)	Antitubercular Agents/chemistry ; Antitubercular Agents/metabolism ; Drug Discovery ; Enzyme Activation/drug effects ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/metabolism ; Escherichia coli/metabolism ; Glycolates/chemistry ; Glyoxylates/chemistry ; Humans ; Isocitrate Lyase/antagonists & inhibitors ; Isomerism ; Models, Molecular ; Mycobacterium tuberculosis/enzymology ; Protein Binding ; Protein Conformation ; Proteomics ; Succinates/chemistry ; Succinates/metabolism ; Thermodynamics ; Tuberculosis/drug therapy
Chemical Substances	Antitubercular Agents ; Enzyme Inhibitors ; Glycolates ; Glyoxylates ; Succinates ; glycolic acid (0WT12SX38S) ; 2,3-epoxysuccinic acid (3272-11-5) ; Isocitrate Lyase (EC 4.1.3.1) ; glyoxylic acid (JQ39C92HH6)
Language	English
Publishing date	2021-03-10
Publishing country	United States
Document type	Journal Article
ISSN	1554-8937
ISSN (online)	1554-8937
DOI	10.1021/acschembio.0c00740
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Dinitrosyl iron complexes (DNICs) as inhibitors of the SARS-CoV-2 main protease.

Pectol, D Chase / DeLaney, Christopher R / Zhu, Jiyun / Mellott, Drake M / Katzfuss, Ardala / Taylor, Zane W / Meek, Thomas D / Darensbourg, Marcetta Y

Chemical communications (Cambridge, England)

2021 Volume 57, Issue 67, Page(s) 8352–8355

Abstract: By repurposing DNICs designed for other medicinal purposes, the possibility of protease inhibition was investigated in silico using AutoDock 4.2.6 (AD4) and in vitro via a FRET protease assay. AD4 was validated as a predictive computational tool for ... ...

Abstract	By repurposing DNICs designed for other medicinal purposes, the possibility of protease inhibition was investigated in silico using AutoDock 4.2.6 (AD4) and in vitro via a FRET protease assay. AD4 was validated as a predictive computational tool for coordinatively unsaturated DNIC binding using the only known crystal structure of a protein-bound DNIC, PDB- (calculation RMSD = 1.77). From the in silico data the dimeric DNICs TGTA-RRE, [(μ-S-TGTA)Fe(NO)
MeSH term(s)	Dose-Response Relationship, Drug ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Humans ; Iron/chemistry ; Iron/pharmacology ; Models, Molecular ; Molecular Structure ; Nitrogen Oxides/chemistry ; Nitrogen Oxides/pharmacology ; Peptide Hydrolases/metabolism ; SARS-CoV-2/drug effects ; SARS-CoV-2/enzymology
Chemical Substances	Enzyme Inhibitors ; Nitrogen Oxides ; dinitrosyl iron complex (68586-27-6) ; Iron (E1UOL152H7) ; Peptide Hydrolases (EC 3.4.-)
Language	English
Publishing date	2021-08-02
Publishing country	England
Document type	Journal Article
ZDB-ID	1472881-3
ISSN	1364-548X ; 1359-7345 ; 0009-241X
ISSN (online)	1364-548X
ISSN	1359-7345 ; 0009-241X
DOI	10.1039/d1cc03103a
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Self-Masked Aldehyde Inhibitors of Human Cathepsin L Are Potent Anti-CoV-2 Agents.

Zhu, Jiyun / Li, Linfeng / Drelich, Aleksandra / Chenna, Bala C / Mellott, Drake M / Taylor, Zane W / Tat, Vivian / Garcia, Christopher Z / Katzfuss, Ardala / Tseng, Chien-Te K / Meek, Thomas D

Frontiers in chemistry

2022 Volume 10, Page(s) 867928

Abstract: Cysteine proteases comprise an important class of drug targets, especially for infectious diseases such as Chagas disease (cruzain) and COVID-19 (3CL protease, cathepsin L). Peptide aldehydes have proven to be potent inhibitors for all of these proteases. ...

Abstract	Cysteine proteases comprise an important class of drug targets, especially for infectious diseases such as Chagas disease (cruzain) and COVID-19 (3CL protease, cathepsin L). Peptide aldehydes have proven to be potent inhibitors for all of these proteases. However, the intrinsic, high electrophilicity of the aldehyde group is associated with safety concerns and metabolic instability, limiting the use of aldehyde inhibitors as drugs. We have developed a novel class of compounds, self-masked aldehyde inhibitors (SMAIs) which are based on the dipeptide aldehyde inhibitor (Cbz-Phe-Phe-CHO,
Language	English
Publishing date	2022-07-04
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2711776-5
ISSN	2296-2646
ISSN	2296-2646
DOI	10.3389/fchem.2022.867928
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Article: Mechanism-Based Inactivation of Mycobacterium tuberculosis Isocitrate Lyase 1 by (2R,3S)-2-Hydroxy-3-(nitromethyl)succinic acid

Mellott, Drake M. / Torres, Dan / Krieger, Inna V. / Cameron, Scott A. / Moghadamchargari, Zahra / Laganowsky, Arthur / Sacchettini, James C. / Meek, Thomas D. / Harris, Lawrence D.

Journal of the American Chemical Society. 2021 Oct. 19, v. 143, no. 42

2021

Abstract: ... efficient mechanism-based inactivator of ICL1 (kᵢₙₐcₜ/KI = (1.3 ± 0.1) × 10³ M–¹ s–¹) with a partition ratio ... will simplify the synthesis of pro-drug forms of 5-NIC for characterization in cell-infection models of M ...

Abstract	The isocitrate lyase paralogs of Mycobacterium tuberculosis (ICL1 and 2) are essential for mycobacterial persistence and constitute targets for the development of antituberculosis agents. We report that (2R,3S)-2-hydroxy-3-(nitromethyl)succinic acid (5-NIC) undergoes apparent retro-aldol cleavage as catalyzed by ICL1 to produce glyoxylate and 3-nitropropionic acid (3-NP), the latter of which is a covalent-inactivating agent of ICL1. Kinetic analysis of this reaction identified that 5-NIC serves as a robust and efficient mechanism-based inactivator of ICL1 (kᵢₙₐcₜ/KI = (1.3 ± 0.1) × 10³ M–¹ s–¹) with a partition ratio <1. Using enzyme kinetics, mass spectrometry, and X-ray crystallography, we identified that the reaction of the 5-NIC-derived 3-NP with the Cys₁₉₁ thiolate of ICL1 results in formation of an ICL1-thiohydroxamate adduct as predicted. One aspect of the design of 5-NIC was to lower its overall charge compared to isocitrate to assist with cell permeability. Accordingly, the absence of the third carboxylate group will simplify the synthesis of pro-drug forms of 5-NIC for characterization in cell-infection models of M. tuberculosis.
Keywords	3-nitropropionic acid ; Mycobacterium tuberculosis ; X-ray diffraction ; enzyme kinetics ; isocitrate lyase ; kinetics ; mass spectrometry ; permeability ; succinic acid
Language	English
Dates of publication	2021-1019
Size	p. 17666-17676.
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.1c07970
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Article ; Online: Mechanism-Based Inactivation of

Mellott, Drake M / Torres, Dan / Krieger, Inna V / Cameron, Scott A / Moghadamchargari, Zahra / Laganowsky, Arthur / Sacchettini, James C / Meek, Thomas D / Harris, Lawrence D

Journal of the American Chemical Society

2021 Volume 143, Issue 42, Page(s) 17666–17676

Abstract: The isocitrate lyase paralogs ... ...

Abstract	The isocitrate lyase paralogs of
MeSH term(s)	Enzyme Inhibitors/chemical synthesis ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/metabolism ; Glyoxylates/chemistry ; Glyoxylates/metabolism ; Isocitrate Lyase/antagonists & inhibitors ; Isocitrate Lyase/chemistry ; Isocitrate Lyase/metabolism ; Kinetics ; Models, Chemical ; Mycobacterium tuberculosis/enzymology ; Nitro Compounds/chemistry ; Nitro Compounds/metabolism ; Propionates/chemistry ; Propionates/metabolism ; Protein Binding ; Succinates/chemical synthesis ; Succinates/chemistry ; Succinates/metabolism
Chemical Substances	Enzyme Inhibitors ; Glyoxylates ; Nitro Compounds ; Propionates ; Succinates ; Isocitrate Lyase (EC 4.1.3.1) ; glyoxylic acid (JQ39C92HH6) ; 3-nitropropionic acid (QY4L0FOX0D)
Language	English
Publishing date	2021-10-19
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.1c07970
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Article ; Online: Self-Masked Aldehyde Inhibitors of Human Cathepsin L Are Potent Anti-CoV-2 Agents

Jiyun Zhu / Linfeng Li / Aleksandra Drelich / Bala C. Chenna / Drake M. Mellott / Zane W. Taylor / Vivian Tat / Christopher Z. Garcia / Ardala Katzfuss / Chien-Te K. Tseng / Thomas D. Meek

Frontiers in Chemistry, Vol

2022 Volume 10

Abstract: ... to be potent anti-SARS-CoV-2 agents in infected mammalian cells (Mellott et al. (2021) ACS Chem. Biol ...

Abstract	Cysteine proteases comprise an important class of drug targets, especially for infectious diseases such as Chagas disease (cruzain) and COVID-19 (3CL protease, cathepsin L). Peptide aldehydes have proven to be potent inhibitors for all of these proteases. However, the intrinsic, high electrophilicity of the aldehyde group is associated with safety concerns and metabolic instability, limiting the use of aldehyde inhibitors as drugs. We have developed a novel class of compounds, self-masked aldehyde inhibitors (SMAIs) which are based on the dipeptide aldehyde inhibitor (Cbz-Phe-Phe-CHO, 1), for which the P1 Phe group contains a 1′-hydroxy group, effectively, an o-tyrosinyl aldehyde (Cbz-Phe-o-Tyr-CHO, 2; (Li et al. (2021) J. Med. Chem. 64, 11,267–11,287)). Compound 2 and other SMAIs exist in aqueous mixtures as stable δ-lactols, and apparent catalysis by the cysteine protease cruzain, the major cysteine protease of Trypanosoma cruzi, results in the opening of the lactol ring to afford the aldehydes which then form reversible thiohemiacetals with the enzyme. These SMAIs are also potent, time-dependent inhibitors of human cathepsin L (Ki = 11–60 nM), an enzyme which shares 36% amino acid identity with cruzain. As inactivators of cathepsin L have recently been shown to be potent anti-SARS-CoV-2 agents in infected mammalian cells (Mellott et al. (2021) ACS Chem. Biol. 16, 642–650), we evaluated SMAIs in VeroE6 and A549/ACE2 cells infected with SARS-CoV-2. These SMAIs demonstrated potent anti-SARS-CoV-2 activity with values of EC50 = 2–8 μM. We also synthesized pro-drug forms of the SMAIs in which the hydroxyl groups of the lactols were O-acylated. Such pro-drug SMAIs resulted in significantly enhanced anti-SARS-CoV-2 activity (EC50 = 0.3–0.6 μM), demonstrating that the O-acylated-SMAIs afforded a level of stability within infected cells, and are likely converted to SMAIs by the action of cellular esterases. Lastly, we prepared and characterized an SMAI in which the sidechain adjacent to the terminal aldehyde is a ...
Keywords	SARS coronavirus-2 ; cathepsin L ; self-masked aldehydes ; reversible covalent inactivation ; COVID-19 ; cysteine proteases ; Chemistry ; QD1-999
Subject code	540
Language	English
Publishing date	2022-07-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
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Article ; Online: Bepridil is potent against SARS-CoV-2 in vitro.

Vatansever, Erol C / Yang, Kai S / Drelich, Aleksandra K / Kratch, Kaci C / Cho, Chia-Chuan / Kempaiah, Kempaiah Rayavara / Hsu, Jason C / Mellott, Drake M / Xu, Shiqing / Tseng, Chien-Te K / Liu, Wenshe Ray

Proceedings of the National Academy of Sciences of the United States of America

2021 Volume 118, Issue 10

Abstract: ... of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (M ...

Abstract	Guided by a computational docking analysis, about 30 Food and Drug Administration/European Medicines Agency (FDA/EMA)-approved small-molecule medicines were characterized on their inhibition of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (M
MeSH term(s)	A549 Cells ; Animals ; Antiviral Agents/pharmacology ; Bepridil/pharmacology ; Chlorocebus aethiops ; Drug Discovery ; Humans ; Molecular Docking Simulation ; Molecular Structure ; SARS-CoV-2/drug effects ; Small Molecule Libraries ; Vero Cells
Chemical Substances	Antiviral Agents ; Small Molecule Libraries ; Bepridil (755BO701MA)
Language	English
Publishing date	2021-02-17
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2012201118
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Article: Bepridil is potent against SARS-CoV-2 In Vitro.

Vatansever, Erol C / Yang, Kai / Kratch, Kaci C / Drelich, Aleksandra / Cho, Chia-Chuan / Mellott, Drake M / Xu, Shiqing / Tseng, Chien-Te K / Liu, Wenshe Ray

bioRxiv : the preprint server for biology

2020

Abstract: ... characterized on their inhibition of the SARS-CoV-2 main protease (M ...

Abstract	Guided by a computational docking analysis, about 30 FDA/EMA-approved small molecule medicines were characterized on their inhibition of the SARS-CoV-2 main protease (M
Keywords	covid19
Language	English
Publishing date	2020-07-27
Publishing country	United States
Document type	Preprint
DOI	10.1101/2020.05.23.112235
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Article: Dinitrosyl iron complexes (DNICs) as inhibitors of the SARS-CoV-2 main protease

Pectol, D. Chase / DeLaney, Christopher R. / Zhu, Jiyun / Mellott, Drake M. / Katzfuss, Ardala / Taylor, Zane W. / Meek, Thomas D. / Darensbourg, Marcetta Y.

Chemical communications. 2021 Aug. 19, v. 57, no. 67

2021

Abstract	By repurposing DNICs designed for other medicinal purposes, the possibility of protease inhibition was investigated in silico using AutoDock 4.2.6 (AD4) and in vitro via a FRET protease assay. AD4 was validated as a predictive computational tool for coordinatively unsaturated DNIC binding using the only known crystal structure of a protein-bound DNIC, PDB–1ZGN (calculation RMSD = 1.77). From the in silico data the dimeric DNICs TGTA–RRE, [(μ-S-TGTA)Fe(NO)₂]₂ (TGTA = 1-thio-β-d-glucose tetraacetate) and TG–RRE, [(μ-S-TG)Fe(NO)₂]₂ (TG = 1-thio-β-d-glucose) were identified as promising leads for inhibition via coordinative inhibition at Cys-145 of the SARS-CoV-2 Main Protease (SC2Mᵖʳᵒ). In vitro studies indicate inhibition of protease activity upon DNIC treatment, with an IC₅₀ of 38 ± 2 μM for TGTA–RRE and 33 ± 2 μM for TG–RRE. This study presents a simple computational method for predicting DNIC–protein interactions; the in vitro study is consistent with in silico leads.
Keywords	computer simulation ; crystal structure ; enzyme activity ; proteinases
Language	English
Dates of publication	2021-0819
Size	p. 8352-8355.
Publishing place	The Royal Society of Chemistry
Document type	Article
ZDB-ID	1472881-3
ISSN	1364-548X ; 1359-7345 ; 0009-241X
ISSN (online)	1364-548X
ISSN	1359-7345 ; 0009-241X
DOI	10.1039/d1cc03103a
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Article ; Online: Peptidomimetic Vinyl Heterocyclic Inhibitors of Cruzain Effect Antitrypanosomal Activity.

Chenna, Bala C / Li, Linfeng / Mellott, Drake M / Zhai, Xiang / Siqueira-Neto, Jair L / Calvet Alvarez, Claudia / Bernatchez, Jean A / Desormeaux, Emily / Alvarez Hernandez, Elizabeth / Gomez, Jana / McKerrow, James H / Cruz-Reyes, Jorge / Meek, Thomas D

Journal of medicinal chemistry

2020 Volume 63, Issue 6, Page(s) 3298–3316

Abstract: Cruzain, an essential cysteine protease of the parasitic protozoan, ...

Abstract	Cruzain, an essential cysteine protease of the parasitic protozoan,
MeSH term(s)	Animals ; Cysteine Endopeptidases/metabolism ; Cysteine Proteinase Inhibitors/chemical synthesis ; Cysteine Proteinase Inhibitors/metabolism ; Cysteine Proteinase Inhibitors/pharmacology ; Drug Design ; Enzyme Assays ; Humans ; Kinetics ; Mice ; Molecular Docking Simulation ; Myoblasts, Cardiac/drug effects ; Peptidomimetics/chemical synthesis ; Peptidomimetics/metabolism ; Peptidomimetics/pharmacology ; Protein Binding ; Protozoan Proteins/antagonists & inhibitors ; Protozoan Proteins/metabolism ; Pyridines/chemical synthesis ; Pyridines/metabolism ; Pyridines/pharmacology ; Pyrimidines/chemical synthesis ; Pyrimidines/metabolism ; Pyrimidines/pharmacology ; Trypanocidal Agents/chemical synthesis ; Trypanocidal Agents/metabolism ; Trypanocidal Agents/pharmacology ; Trypanosoma brucei brucei/drug effects ; Trypanosoma cruzi/drug effects ; Vinyl Compounds/chemical synthesis ; Vinyl Compounds/metabolism ; Vinyl Compounds/pharmacology
Chemical Substances	Cysteine Proteinase Inhibitors ; Peptidomimetics ; Protozoan Proteins ; Pyridines ; Pyrimidines ; Trypanocidal Agents ; Vinyl Compounds ; Cysteine Endopeptidases (EC 3.4.22.-) ; cruzipain (EC 3.4.22.51)
Language	English
Publishing date	2020-03-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.9b02078
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