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Article ; Online: Discovery of Triple Inhibitors of Both SARS-CoV-2 Proteases and Human Cathepsin L

Ittipat Meewan / Jacob Kattoula / Julius Y. Kattoula / Danielle Skinner / Pavla Fajtová / Miriam A. Giardini / Brendon Woodworth / James H. McKerrow / Jair Lage de Siqueira-Neto / Anthony J. O’Donoghue / Ruben Abagyan

Pharmaceuticals, Vol 15, Iss 744, p

2022 Volume 744

Abstract: One inhibitor of the main SARS-CoV-2 protease has been approved recently by the FDA, yet it targets only SARS-CoV-2 main protease (Mpro). Here, we discovered inhibitors containing thiuram disulfide or dithiobis-(thioformate) tested against three key ... ...

Abstract	One inhibitor of the main SARS-CoV-2 protease has been approved recently by the FDA, yet it targets only SARS-CoV-2 main protease (Mpro). Here, we discovered inhibitors containing thiuram disulfide or dithiobis-(thioformate) tested against three key proteases involved in SARS-CoV-2 replication, including Mpro, SARS-CoV-2 papain-like protease (PLpro), and human cathepsin L. The use of thiuram disulfide and dithiobis-(thioformate) covalent inhibitor warheads was inspired by an idea to find a better alternative than disulfiram, an approved treatment for chronic alcoholism that is currently in phase 2 clinical trials against SARS-CoV-2. Our goal was to find more potent inhibitors that target both viral proteases and one essential human protease to reduce the dosage, improve the efficacy, and minimize the adverse effects associated with these agents. We found that compounds coded as RI175, RI173, and RI172 were the most potent inhibitors in an enzymatic assay against SARS-CoV-2 Mpro, SARS-CoV-2 PLpro, and human cathepsin L, with IC 50 s of 300, 200, and 200 nM, which is about 5-, 19-, and 11-fold more potent than disulfiram, respectively. In addition, RI173 was tested against SARS-CoV-2 in a cell-based and toxicity assay and was shown to have a greater antiviral effect than disulfiram. The identified compounds demonstrated the promising potential of thiuram disulfide or dithiobis-(thioformate) as a reactive functional group in small molecules that could be further developed for treatment of the COVID-19 virus or related variants.
Keywords	COVID-19 drug candidates ; multiple protease inhibitors ; disulfiram ; thiuram disulfide ; dithiobis-(thioformate) ; SARS-CoV-2 main protease ; Medicine ; R ; Pharmacy and materia medica ; RS1-441
Subject code	572
Language	English
Publishing date	2022-06-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Giant magnetoresistive biosensors for real-time quantitative detection of protease activity

Sandeep Adem / Sonal Jain / Michael Sveiven / Xiahan Zhou / Anthony J. O’Donoghue / Drew A. Hall

Scientific Reports, Vol 10, Iss 1, Pp 1-

2020 Volume 10

Abstract: Abstract Proteases are enzymes that cleave proteins and are crucial to physiological processes such as digestion, blood clotting, and wound healing. Unregulated protease activity is a biomarker of several human diseases. Synthetic peptides that are ... ...

Abstract	Abstract Proteases are enzymes that cleave proteins and are crucial to physiological processes such as digestion, blood clotting, and wound healing. Unregulated protease activity is a biomarker of several human diseases. Synthetic peptides that are selectively hydrolyzed by a protease of interest can be used as reporter substrates of unregulated protease activity. We developed an activity-based protease sensor by immobilizing magnetic nanoparticles (MNPs) to the surface of a giant magnetoresistive spin-valve (GMR SV) sensor using peptides. Cleavage of these peptides by a protease releases the magnetic nanoparticles resulting in a time-dependent change in the local magnetic field. Using this approach, we detected a significant release of MNPs after 3.5 minutes incubation using just 4 nM of the cysteine protease, papain. In addition, we show that proteases in healthy human urine do not release the MNPs, however addition of 20 nM of papain to the urine samples resulted in a time-dependent change in magnetoresistance. This study lays the foundation for using GMR SV sensors as a platform for real-time, quantitative detection of protease activity in biological fluids.
Keywords	Medicine ; R ; Science ; Q
Subject code	540
Language	English
Publishing date	2020-05-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Discovery of New Inhibitors of Hepatitis C Virus NS3/4A Protease and Its D168A Mutant

Ittipat Meewan / Xingquan Zhang / Suchismita Roy / Carlo Ballatore / Anthony J. O’Donoghue / Robert T. Schooley / Ruben Abagyan

ACS Omega, Vol 4, Iss 16, Pp 16999-

2019 Volume 17008

Keywords	Chemistry ; QD1-999
Language	English
Publishing date	2019-10-01T00:00:00Z
Publisher	American Chemical Society
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Targeting proteasomes in infectious organisms to combat disease

BiboâVerdugo, Betsaida / Anthony J. O'Donoghue / Conor R. Caffrey / Zhenze Jiang

FEBS journal. 2017 May, v. 284, no. 10

2017

Abstract: Proteasomes are multisubunit, energyâdependent, proteolytic complexes that play an essential role in intracellular protein turnover. They are present in eukaryotes, archaea, and in some actinobacteria species. Inhibition of proteasome activity has ... ...

Abstract	Proteasomes are multisubunit, energyâdependent, proteolytic complexes that play an essential role in intracellular protein turnover. They are present in eukaryotes, archaea, and in some actinobacteria species. Inhibition of proteasome activity has emerged as a powerful strategy for anticancer therapy and three drugs have been approved for treatment of multiple myeloma. These compounds react covalently with a threonine residue located in the active site of a proteasome subunit to block protein degradation. Proteasomes in pathogenic organisms such as Mycobacterium tuberculosis and Plasmodium falciparum also have a nucleophilic threonine residue in the proteasome active site and are therefore sensitive to these anticancer drugs. This review summarizes efforts to validate the proteasome in pathogenic organisms as a therapeutic target. We describe several strategies that have been used to develop inhibitors with increased potency and selectivity for the pathogen proteasome relative to the human proteasome. In addition, we highlight a cellâbased chemical screening approach that identified a potent, allosteric inhibitor of proteasomes found in Leishmania and Trypanosoma species. Finally, we discuss the development of proteasome inhibitors as antiâinfective agents.
Keywords	active sites ; anti-infective agents ; antineoplastic agents ; Archaea ; chemical bonding ; eukaryotic cells ; humans ; Leishmania ; Lewis bases ; Mycobacterium tuberculosis ; myeloma ; pathogens ; Plasmodium falciparum ; proteasome endopeptidase complex ; proteasome inhibitors ; protein degradation ; protein metabolism ; proteolysis ; screening ; therapeutics ; threonine ; Trypanosoma
Language	English
Dates of publication	2017-05
Size	p. 1503-1517.
Publishing place	John Wiley & Sons, Ltd
Document type	Article
Note	REVIEW
ZDB-ID	2173655-8
ISSN	1742-4658 ; 1742-464X
ISSN (online)	1742-4658
ISSN	1742-464X
DOI	10.1111/febs.14029
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: High-Resolution Mass Spectrometry-Based Approaches for the Detection and Quantification of Peptidase Activity in Plasma

Elisa Maffioli / Zhenze Jiang / Simona Nonnis / Armando Negri / Valentina Romeo / Christopher B. Lietz / Vivian Hook / Giuseppe Ristagno / Giuseppe Baselli / Erik B. Kistler / Federico Aletti / Anthony J. O’Donoghue / Gabriella Tedeschi

Molecules, Vol 25, Iss 4071, p

2020 Volume 4071

Abstract: Proteomic technologies have identified 234 peptidases in plasma but little quantitative information about the proteolytic activity has been uncovered. In this study, the substrate profile of plasma proteases was evaluated using two nano-LC-ESI-MS/MS ... ...

Abstract	Proteomic technologies have identified 234 peptidases in plasma but little quantitative information about the proteolytic activity has been uncovered. In this study, the substrate profile of plasma proteases was evaluated using two nano-LC-ESI-MS/MS methods. Multiplex substrate profiling by mass spectrometry (MSP-MS) quantifies plasma protease activity in vitro using a global and unbiased library of synthetic peptide reporter substrates, and shotgun peptidomics quantifies protein degradation products that have been generated in vivo by proteases. The two approaches gave complementary results since they both highlight key peptidase activities in plasma including amino- and carboxypeptidases with different substrate specificity profiles. These assays provide a significant advantage over traditional approaches, such as fluorogenic peptide reporter substrates, because they can detect active plasma proteases in a global and unbiased manner, in comparison to detecting select proteases using specific reporter substrates. We discovered that plasma proteins are cleaved by endoproteases and these peptide products are subsequently degraded by amino- and carboxypeptidases. The exopeptidases are more active and stable in plasma and therefore were found to be the most active proteases in the in vitro assay. The protocols presented here set the groundwork for studies to evaluate changes in plasma proteolytic activity in shock.
Keywords	peptidomics ; mass spectrometry ; plasma ; aminopeptidase ; carboxypeptidase ; endoprotease ; Organic chemistry ; QD241-441
Subject code	540
Language	English
Publishing date	2020-09-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Mutant Presenilin 1 Dysregulates Exosomal Proteome Cargo Produced by Human-Induced Pluripotent Stem Cell Neurons

Sonia Podvin / Alexander Jones / Qing Liu / Brent Aulston / Charles Mosier / Janneca Ames / Charisse Winston / Christopher B. Lietz / Zhenze Jiang / Anthony J. O’Donoghue / Tsuneya Ikezu / Robert A. Rissman / Shauna H. Yuan / Vivian Hook

ACS Omega, Vol 6, Iss 20, Pp 13033-

2021 Volume 13056

Keywords	Chemistry ; QD1-999
Language	English
Publishing date	2021-05-01T00:00:00Z
Publisher	American Chemical Society
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: SmSP2

Adrian Leontovyč / Lenka Ulrychová / Anthony J O'Donoghue / Jiří Vondrášek / Lucie Marešová / Martin Hubálek / Pavla Fajtová / Marta Chanová / Zhenze Jiang / Charles S Craik / Conor R Caffrey / Michael Mareš / Jan Dvořák / Martin Horn

PLoS Neglected Tropical Diseases, Vol 12, Iss 4, p e

A serine protease secreted by the blood fluke pathogen Schistosoma mansoni with anti-hemostatic properties.

2018 Volume 0006446

Abstract: BACKGROUND:Serine proteases are important virulence factors for many pathogens. Recently, we discovered a group of trypsin-like serine proteases with domain organization unique to flatworm parasites and containing a thrombospondin type 1 repeat (TSR-1). ... ...

Abstract	BACKGROUND:Serine proteases are important virulence factors for many pathogens. Recently, we discovered a group of trypsin-like serine proteases with domain organization unique to flatworm parasites and containing a thrombospondin type 1 repeat (TSR-1). These proteases are recognized as antigens during host infection and may prove useful as anthelminthic vaccines, however their molecular characteristics are under-studied. Here, we characterize the structural and proteolytic attributes of serine protease 2 (SmSP2) from Schistosoma mansoni, one of the major species responsible for the tropical infectious disease, schistosomiasis. METHODOLOGY/PRINCIPAL FINDINGS:SmSP2 comprises three domains: a histidine stretch, TSR-1 and a serine protease domain. The cleavage specificity of recombinant SmSP2 was determined using positional scanning and multiplex combinatorial libraries and the determinants of specificity were identified with 3D homology models, demonstrating a trypsin-like endopeptidase mode of action. SmSP2 displayed restricted proteolysis on protein substrates. It activated tissue plasminogen activator and plasminogen as key components of the fibrinolytic system, and released the vasoregulatory peptide, kinin, from kininogen. SmSP2 was detected in the surface tegument, esophageal glands and reproductive organs of the adult parasite by immunofluorescence microscopy, and in the excretory/secretory products by immunoblotting. CONCLUSIONS/SIGNIFICANCE:The data suggest that SmSP2 is secreted, functions at the host-parasite interface and contributes to the survival of the parasite by manipulating host vasodilatation and fibrinolysis. SmSP2 may be, therefore, a potential target for anti-schistosomal therapy.
Keywords	Arctic medicine. Tropical medicine ; RC955-962 ; Public aspects of medicine ; RA1-1270
Subject code	572
Language	English
Publishing date	2018-04-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Native metabolomics identifies the rivulariapeptolide family of protease inhibitors

Raphael Reher / Allegra T. Aron / Pavla Fajtová / Paolo Stincone / Berenike Wagner / Alicia I. Pérez-Lorente / Chenxi Liu / Ido Y. Ben Shalom / Wout Bittremieux / Mingxun Wang / Kyowon Jeong / Marie L. Matos-Hernandez / Kelsey L. Alexander / Eduardo J. Caro-Diaz / C. Benjamin Naman / J. H. William Scanlan / Phil M. M. Hochban / Wibke E. Diederich / Carlos Molina-Santiago /

Diego Romero / Khaled A. Selim / Peter Sass / Heike Brötz-Oesterhelt / Chambers C. Hughes / Pieter C. Dorrestein / Anthony J. O’Donoghue / William H. Gerwick / Daniel Petras

Nature Communications, Vol 13, Iss 1, Pp 1-

2022 Volume 12

Abstract: Bioactivity-guided isolation of specialized metabolites is an iterative process. Here, the authors demonstrate a native metabolomics approach that allows for fast screening of complex metabolite extracts against a protein of interest and simultaneous ... ...

Abstract	Bioactivity-guided isolation of specialized metabolites is an iterative process. Here, the authors demonstrate a native metabolomics approach that allows for fast screening of complex metabolite extracts against a protein of interest and simultaneous structure annotation.
Keywords	Science ; Q
Language	English
Publishing date	2022-08-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Substrate Specificity of Cysteine Proteases Beyond the S2 Pocket

Ileana Corvo / Florencia Ferraro / Alicia Merlino / Kathrin Zuberbühler / Anthony J. O'Donoghue / Lucía Pastro / Natalia Pi-Denis / Tatiana Basika / Leda Roche / James H. McKerrow / Charles S. Craik / Conor R. Caffrey / José F. Tort

Frontiers in Molecular Biosciences, Vol

Mutagenesis and Molecular Dynamics Investigation of Fasciola hepatica Cathepsins L

2018 Volume 5

Abstract: Cysteine proteases are widespread in all life kingdoms, being central to diverse physiological processes based on a broad range of substrate specificity. Paralogous Fasciola hepatica cathepsin L proteases are essential to parasite invasion, tissue ... ...

Abstract	Cysteine proteases are widespread in all life kingdoms, being central to diverse physiological processes based on a broad range of substrate specificity. Paralogous Fasciola hepatica cathepsin L proteases are essential to parasite invasion, tissue migration and reproduction. In spite of similarities in their overall sequence and structure, these enzymes often exhibit different substrate specificity. These preferences are principally determined by the amino acid composition of the active site's S2 subsite (pocket) of the enzyme that interacts with the substrate P2 residue (Schetcher and Berger nomenclature). Although secreted FhCL1 accommodates aliphatic residues in the S2 pocket, FhCL2 is also efficient in cleaving proline in that position. To understand these differences, we engineered the FhCL1 S2 subsite at three amino acid positions to render it identical to that present in FhCL2. The substitutions did not produce the expected increment in proline accommodation in P2. Rather, they decreased the enzyme's catalytic efficiency toward synthetic peptides. Nonetheless, a change in the P3 specificity was associated with the mutation of Leu67 to Tyr, a hinge residue between the S2 and S3 subsites that contributes to the accommodation of Gly in S3. Molecular dynamic simulations highlighted changes in the spatial distribution and secondary structure of the S2 and S3 pockets of the mutant FhCL1 enzymes. The reduced affinity and catalytic efficiency of the mutant enzymes may be due to a narrowing of the active site cleft that hinders the accommodation of substrates. Because the variations in the enzymatic activity measured could not be exclusively allocated to those residues lining the active site, other more external positions might modulate enzyme conformation, and, therefore, catalytic activity.
Keywords	Fasciola hepatica ; cathepsin L ; active site conformation ; S2 pocket ; mutagenesis ; molecular dynamics simulation ; Biology (General) ; QH301-705.5
Subject code	540
Language	English
Publishing date	2018-04-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Cysteine and Aspartyl Proteases Contribute to Protein Digestion in the Gut of Freshwater Planaria.

Louise S Goupil / Sam L Ivry / Ivy Hsieh / Brian M Suzuki / Charles S Craik / Anthony J O'Donoghue / James H McKerrow

PLoS Neglected Tropical Diseases, Vol 10, Iss 8, p e

2016 Volume 0004893

Abstract: Proteases perform numerous vital functions in flatworms, many of which are likely to be conserved throughout the phylum Platyhelminthes. Within this phylum are several parasitic worms that are often poorly characterized due to their complex life-cycles ... ...

Abstract	Proteases perform numerous vital functions in flatworms, many of which are likely to be conserved throughout the phylum Platyhelminthes. Within this phylum are several parasitic worms that are often poorly characterized due to their complex life-cycles and lack of responsiveness to genetic manipulation. The flatworm Schmidtea mediterranea, or planaria, is an ideal model organism to study the complex role of protein digestion due to its simple life cycle and amenability to techniques like RNA interference (RNAi). In this study, we were interested in deconvoluting the digestive protease system that exists in the planarian gut. To do this, we developed an alcohol-induced regurgitation technique to enrich for the gut enzymes in S. mediterranea. Using a panel of fluorescent substrates, we show that this treatment produces a sharp increase in proteolytic activity. These enzymes have broad yet diverse substrate specificity profiles. Proteomic analysis of the gut contents revealed the presence of cysteine and metallo-proteases. However, treatment with class-specific inhibitors showed that aspartyl and cysteine proteases are responsible for the majority of protein digestion. Specific RNAi knockdown of the cathepsin B-like cysteine protease (SmedCB) reduced protein degradation in vivo. Immunohistochemistry and whole-mount in situ hybridization (WISH) confirmed that the full-length and active forms of SmedCB are found in secretory cells surrounding the planaria intestinal lumen. Finally, we show that the knockdown of SmedCB reduces the speed of tissue regeneration. Defining the roles of proteases in planaria can provide insight to functions of conserved proteases in parasitic flatworms, potentially uncovering drug targets in parasites.
Keywords	Arctic medicine. Tropical medicine ; RC955-962 ; Public aspects of medicine ; RA1-1270
Subject code	572
Language	English
Publishing date	2016-08-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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