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  1. Article ; Online: A Computer-Aided Approach for the Discovery of D-Peptides as Inhibitors of SARS-CoV-2 Main Protease

    Jorge E. Hernández González / Raphael J. Eberle / Dieter Willbold / Mônika A. Coronado

    Frontiers in Molecular Biosciences, Vol

    2022  Volume 8

    Abstract: The SARS-CoV-2 main protease, also known as 3-chymotrypsin-like protease (3CLpro), is a cysteine protease responsible for the cleavage of viral polyproteins pp1a and pp1ab, at least, at eleven conserved sites, which leads to the formation of mature ... ...

    Abstract The SARS-CoV-2 main protease, also known as 3-chymotrypsin-like protease (3CLpro), is a cysteine protease responsible for the cleavage of viral polyproteins pp1a and pp1ab, at least, at eleven conserved sites, which leads to the formation of mature nonstructural proteins essential for the replication of the virus. Due to its essential role, numerous studies have been conducted so far, which have confirmed 3CLpro as an attractive drug target to combat Covid-19 and have reported a vast number of inhibitors and their co-crystal structures. Despite all the ongoing efforts, D-peptides, which possess key advantages over L-peptides as therapeutic agents, have not been explored as potential drug candidates against 3CLpro. The current work fills this gap by reporting an in silico approach for the discovery of D-peptides capable of inhibiting 3CLpro that involves structure-based virtual screening (SBVS) of an in-house library of D-tripeptides and D-tetrapeptides into the protease active site and subsequent rescoring steps, including Molecular Mechanics Generalized-Born Surface Area (MM-GBSA) free energy calculations and molecular dynamics (MD) simulations. In vitro enzymatic assays conducted for the four top-scoring D-tetrapeptides at 20 μM showed that all of them caused 55–85% inhibition of 3CLpro activity, thus highlighting the suitability of the devised approach. Overall, our results present a promising computational strategy to identify D-peptides capable of inhibiting 3CLpro, with broader application in problems involving protein inhibition.
    Keywords SARS-CoV-2 ; 3CLpro ; D-peptide ; virtual screening ; molecular dynamics simulation ; Biology (General) ; QH301-705.5
    Subject code 540
    Language English
    Publishing date 2022-01-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Design of D-Amino Acids SARS-CoV-2 Main Protease Inhibitors Using the Cationic Peptide from Rattlesnake Venom as a Scaffold

    Raphael J. Eberle / Ian Gering / Markus Tusche / Philipp N. Ostermann / Lisa Müller / Ortwin Adams / Heiner Schaal / Danilo S. Olivier / Marcos S. Amaral / Raghuvir K. Arni / Dieter Willbold / Mônika A. Coronado

    Pharmaceuticals, Vol 15, Iss 540, p

    2022  Volume 540

    Abstract: The C30 endopeptidase (3C-like protease; 3CL pro ) is essential for the life cycle of SARS-CoV-2 (severe acute respiratory syndrome-coronavirus-2) since it plays a pivotal role in viral replication and transcription and, hence, is a promising drug target. ...

    Abstract The C30 endopeptidase (3C-like protease; 3CL pro ) is essential for the life cycle of SARS-CoV-2 (severe acute respiratory syndrome-coronavirus-2) since it plays a pivotal role in viral replication and transcription and, hence, is a promising drug target. Molecules isolated from animals, insects, plants, or microorganisms can serve as a scaffold for the design of novel biopharmaceutical products. Crotamine, a small cationic peptide from the venom of the rattlesnake Crotalus durissus terrificus , has been the focus of many studies since it exhibits activities such as analgesic, in vitro antibacterial, and hemolytic activities. The crotamine derivative L-peptides (L-CDP) that inhibit the 3CL protease in the low µM range were examined since they are susceptible to proteolytic degradation; we explored the utility of their D-enantiomers form. Comparative uptake inhibition analysis showed D-CDP as a promising prototype for a D-peptide-based drug. We also found that the D-peptides can impair SARS-CoV-2 replication in vivo, probably targeting the viral protease 3CL pro .
    Keywords SARS-CoV-2 ; COVID-19 ; 3CL pro ; main protease ; inhibitor ; crotamine derivative peptides ; Medicine ; R ; Pharmacy and materia medica ; RS1-441
    Language English
    Publishing date 2022-04-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Book ; Online: Novel Inhibitors of the Main Protease of SARS-CoV-2 Identified via a Molecular Dynamics Simulation-Guided in Vitro Assay

    Jennifer Loschwitz / Anna Jäckering / Monika Keutmann / Maryam Olagunju / Raphael J. Eberle / Monika A. Coronado / Olujide O. Olubiyi / Birgit Strodel

    2020  

    Abstract: For the COVID-19 pandemic caused by SARS-CoV-2, there are currently no effective drugs or vaccines to treat this coronavirus infection. In this study, we focus on the main protease enzyme of SARS-CoV-2, 3CL pro , which is critical for viral replication. ... ...

    Abstract For the COVID-19 pandemic caused by SARS-CoV-2, there are currently no effective drugs or vaccines to treat this coronavirus infection. In this study, we focus on the main protease enzyme of SARS-CoV-2, 3CL pro , which is critical for viral replication. We employ explicit solvent molecular dynamics simulations of about 150 compounds docked into 3CL pro ’s binding site and that had emerged as good main protease ligands from our previous in silico screening of over 1.2 million compounds. By incoporating protein dynamics and applying a range of structural descriptors, such as the ability to form specific contacts with the catalytic dyad residues of 3CL pro and the structural fluctuations of the ligands in the binding site, we are able to further refine our compound selection. Fourteen compounds including estradiol shown to be the most promising based on our calculations were procured and screened against recombinant 3CL pro in a fluorescence assay. Eight of these compounds have significant activity in inhibiting the SARS-CoV-2 main protease. Among these are corilagin, a gallotannin, and lurasidone, an antipsychotic drug, which emerged as the most promising natural product and drug, respectively, and might thus be candidates for drug repurposing for the treatment of COVID-19. In addition, we also tested the inhibitory activity of testosterone, and our results reveal testosterone as possessing moderate inhibitory potency against the 3CL pro enzyme, which may thus provide an explanation why older men are more severely affected by COVID-19.
    Keywords Bioinformatics and Computational Biology ; Drug Discovery and Drug Delivery Systems ; COVID-19 ; 3CLpro ; viral replication inhibition ; MD simulations ; enzyme inhibition assay ; natural products ; drug repurposing ; covid19
    Subject code 540
    Publishing date 2020-11-09T09:45:33Z
    Document type Book ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: P-I metalloproteinases and L-amino acid oxidases from Bothrops species inhibit angiogenesis

    Shreesha K. Bhat / Manjunath B. Joshi / Sampara Vasishta / Rajesh N. Jagadale / Setlur G. Biligiri / Monika A. Coronado / Raghuvir K. Arni / Kapaettu Satyamoorthy

    Journal of Venomous Animals and Toxins including Tropical Diseases, Vol

    2021  Volume 27

    Abstract: Abstract Background: Snake venoms are composed of pharmacologically active proteins that are evolutionarily diverse, stable and specific to targets. Hence, venoms have been explored as a source of bioactive molecules in treating numerous diseases. Recent ...

    Abstract Abstract Background: Snake venoms are composed of pharmacologically active proteins that are evolutionarily diverse, stable and specific to targets. Hence, venoms have been explored as a source of bioactive molecules in treating numerous diseases. Recent evidences suggest that snake venom proteins may affect the formation of new blood vessels. Excessive angiogenesis has been implicated in several pathologies including tumours, diabetic retinopathy, arthritis, inter alia. In the present study, we have examined the effects of P-I metalloproteinases isolated from Bothrops moojeni (BmMP-1) and Bothrops atrox (BaMP-1) and L-amino acid oxidases (LAAO) isolated from B. moojeni (BmLAAO) and B. atrox (BaLAAO) on biochemical and functional aspects of angiogenesis. Methods: P-I metalloproteinases and LAAO were purified from venom by molecular size exclusion and ion-exchange chromatography and subsequently confirmed using mass spectrometry. The P-I metalloproteinases were characterized by azocaseinolytic, fibrinogenolytic and gelatinase activity and LAAO activity was assessed by enzyme activity on L-amino acids. Influence of these proteins on apoptosis and cell cycle in endothelial cells was analysed by flow cytometry. The angiogenic activity was determined by in vitro 3D spheroid assay, Matrigel tube forming assay, and in vivo agarose plug transformation in mice. Results: P-I metalloproteinases exhibited azocaseinolytic activity, cleaved α and partially β chain of fibrinogen, and displayed catalytic activity on gelatin. LAAO showed differential activity on L-amino acids. Flow cytometry analysis indicated that both P-I metalloproteinases and LAAO arrested the cells in G0/G1 phase and further induced both necrosis and apoptosis in endothelial cells. In vitro, P-I metalloproteinases and LAAO exhibited significant anti-angiogenic properties in 3D spheroid and Matrigel models by reducing sprout outgrowth and tube formation. Using agarose plug transplants in mice harbouring P-I metalloproteinases and LAAO we demonstrated a ...
    Keywords P-I metalloproteinases ; LAAO ; Bothrops ; Anti-angiogenic ; Snake venom ; Arctic medicine. Tropical medicine ; RC955-962 ; Toxicology. Poisons ; RA1190-1270 ; Zoology ; QL1-991
    Subject code 570
    Language English
    Publishing date 2021-08-01T00:00:00Z
    Publisher SciELO
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: In vitro study of Hesperetin and Hesperidin as inhibitors of zika and chikungunya virus proteases.

    Raphael J Eberle / Danilo S Olivier / Carolina C Pacca / Clarita M S Avilla / Mauricio L Nogueira / Marcos S Amaral / Dieter Willbold / Raghuvir K Arni / Monika A Coronado

    PLoS ONE, Vol 16, Iss 3, p e

    2021  Volume 0246319

    Abstract: The potential outcome of flavivirus and alphavirus co-infections is worrisome due to the development of severe diseases. Hundreds of millions of people worldwide live under the risk of infections caused by viruses like chikungunya virus (CHIKV, genus ... ...

    Abstract The potential outcome of flavivirus and alphavirus co-infections is worrisome due to the development of severe diseases. Hundreds of millions of people worldwide live under the risk of infections caused by viruses like chikungunya virus (CHIKV, genus Alphavirus), dengue virus (DENV, genus Flavivirus), and zika virus (ZIKV, genus Flavivirus). So far, neither any drug exists against the infection by a single virus, nor against co-infection. The results described in our study demonstrate the inhibitory potential of two flavonoids derived from citrus plants: Hesperetin (HST) against NS2B/NS3pro of ZIKV and nsP2pro of CHIKV and, Hesperidin (HSD) against nsP2pro of CHIKV. The flavonoids are noncompetitive inhibitors and the determined IC50 values are in low µM range for HST against ZIKV NS2B/NS3pro (12.6 ± 1.3 µM) and against CHIKV nsP2pro (2.5 ± 0.4 µM). The IC50 for HSD against CHIKV nsP2pro was 7.1 ± 1.1 µM. The calculated ligand efficiencies for HST were > 0.3, which reflect its potential to be used as a lead compound. Docking and molecular dynamics simulations display the effect of HST and HSD on the protease 3D models of CHIKV and ZIKV. Conformational changes after ligand binding and their effect on the substrate-binding pocket of the proteases were investigated. Additionally, MTT assays demonstrated a very low cytotoxicity of both the molecules. Based on our results, we assume that HST comprise a chemical structure that serves as a starting point molecule to develop a potent inhibitor to combat CHIKV and ZIKV co-infections by inhibiting the virus proteases.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2021-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article: Biochemical and biophysical characterization of a mycoredoxin protein glutaredoxin A1 from Corynebacterium pseudotuberculosis

    Eberle, Raphael J / Fabio R. de Moraes / Liege A. Kawai / Ljubica Tasic / Monika A. Coronado / Raghuvir K. Arni

    International journal of biological macromolecules. 2018 Feb., v. 107

    2018  

    Abstract: Glutaredoxin A1 from Corynebacterium pseudotuberculosis was shown to be a mycoredoxin protein. In this study, we established a process to overexpress and purify glutaredoxin A1. The aim of this study was the investigation of the Glutaredoxin A1 from C. ... ...

    Abstract Glutaredoxin A1 from Corynebacterium pseudotuberculosis was shown to be a mycoredoxin protein. In this study, we established a process to overexpress and purify glutaredoxin A1. The aim of this study was the investigation of the Glutaredoxin A1 from C. pseudotuberculosis behavior under different redox environments and the identification of lead molecules, which can be used for specific inhibitor development for this protein family. A quantitative assay was performed measuring the rate of insulin reduction spectrophotometrically at 640nm through turbidity formation from the precipitation of the free insulin. Glutaredoxin A1, at 5μM concentration, accelerated the reduction process of 0.2mM insulin and 1mM DTT. The pH optimum of the reaction was 7.4. In the presence of DTT and ESH the glutaredoxin A1 presents similar activity, and its activity is reduced by 50% in the presence of GSH. Additional function for ESH in the redox metabolism of C. pseudotuberculosis is suggested. A combined STD and Chemical Shift – NMR approach was employed to study the effects of potential inhibitors on the structure of glutaredoxin A1 from Corynebacterium pseudotuberculosis. The inhibitory potential of four ligands (heparin, suramin, hesperetin – Hst, and hesperidin - Hsp) against glutaredoxin A1 is discussed.
    Keywords Corynebacterium pseudotuberculosis ; heparin ; hesperetin ; hesperidin ; insulin ; ligands ; metabolism ; nuclear magnetic resonance spectroscopy ; pH ; suramin ; turbidity
    Language English
    Dates of publication 2018-02
    Size p. 1999-2007.
    Publishing place Elsevier B.V.
    Document type Article
    ZDB-ID 282732-3
    ISSN 1879-0003 ; 0141-8130
    ISSN (online) 1879-0003
    ISSN 0141-8130
    DOI 10.1016/j.ijbiomac.2017.10.063
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  7. Article ; Online: Binding studies of a putative C. pseudotuberculosis target protein from Vitamin B12 Metabolism

    Rafaela dos S. Peinado / Danilo S. Olivier / Raphael J. Eberle / Fabio R. de Moraes / Marcos S. Amaral / Raghuvir K. Arni / Monika A. Coronado

    Scientific Reports, Vol 9, Iss 1, Pp 1-

    2019  Volume 13

    Abstract: Abstract Vitamin B12 acts as a cofactor for various metabolic reactions important in living organisms. The Vitamin B12 biosynthesis is restricted to prokaryotes, which means, all eukaryotic organisms must acquire this molecule through diet. This study ... ...

    Abstract Abstract Vitamin B12 acts as a cofactor for various metabolic reactions important in living organisms. The Vitamin B12 biosynthesis is restricted to prokaryotes, which means, all eukaryotic organisms must acquire this molecule through diet. This study presents the investigation of Vitamin B12 metabolism and the characterization of precorrin-4 C(11)-methyltransferase (CobM), an enzyme involved in the biosynthesis of Vitamin B12 in Corynebacterium pseudotuberculosis. The analysis of the C. pseudotuberculosis genome identified two Vitamin B12-dependent pathways, which can be strongly affected by a disrupted vitamin metabolism. Molecular dynamics, circular dichroism, and NMR-STD experiments identified regions in CobM that undergo conformational changes after s-adenosyl-L-methionine binding to promote the interaction of precorrin-4, a Vitamin B12 precursor. The binding of s-adenosyl-L-methionine was examined along with the competitive binding of adenine, dATP, and suramin. Based on fluorescence spectroscopy experiments the dissociation constant for the four ligands and the target protein could be determined; SAM (1.4 ± 0.7 µM), adenine (17.8 ± 1.5 µM), dATP (15.8 ± 2.0 µM), and Suramin (6.3 ± 1.1 µM). The results provide rich information for future investigations of potential drug targets within the C. pseudotuberculosis’s Vitamin B12 metabolism and related pathways to reduce the pathogen’s virulence in its hosts.
    Keywords Medicine ; R ; Science ; Q
    Subject code 570
    Language English
    Publishing date 2019-04-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
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  8. Article: Inhibition of thioredoxin A1 from Corynebacterium pseudotuberculosis by polyanions and flavonoids

    Eberle, Raphael J / Danilo Olivier / Fabio R. de Moraes / Liege A. Kawai / Ljubica Tasic / Marcos S. do Amaral / Monika A. Coronado / Raghuvir K. Arni

    International journal of biological macromolecules. 2018 Oct. 01, v. 117

    2018  

    Abstract: In pathogens, the thioredoxin system forms part of the defense against oxidative stress and ensures the formation of the proper disulfide bonds to ensure protein function. In Corynebacterium pseudotuberculosis, the role and mechanism of TrxA1 has not ... ...

    Abstract In pathogens, the thioredoxin system forms part of the defense against oxidative stress and ensures the formation of the proper disulfide bonds to ensure protein function. In Corynebacterium pseudotuberculosis, the role and mechanism of TrxA1 has not been elucidated, but, the significant homology among different Trxs and the conservation of the residues that form their active sites underline the importance of the Trx systems. Proteins involved in redox metabolism and low molecular weight thiols, which might interact with them, become attractive targets to modulate the activity of pathogens.The activity of the protein was investigated using a turbidimetric assay system. The influence of different pH and low molecular weight thiols were tested. Additionally, this assay was used to investigate the inhibitory potential of ligands from different molecular families, such as, polyanions (suramin and heparin) and flavonoids (hesperetin and hesperidin). All four compounds showed inhibition of the protein activity by approximately 80%. The interactions between these compounds and Cp-TrxA1 were investigated using CD spectroscopy, NMR, molecular docking and dynamics. Our results demonstrate that suramin and hesperetin can serve as lead molecules for the development of specific inhibitors for the C. pseudotuberculosis TrxA1.
    Keywords active sites ; anions ; circular dichroism spectroscopy ; Corynebacterium pseudotuberculosis ; disulfide bonds ; heparin ; hesperetin ; hesperidin ; ligands ; metabolism ; molecular models ; molecular weight ; nuclear magnetic resonance spectroscopy ; oxidative stress ; pathogens ; pH ; proteins ; suramin ; thiols ; thioredoxins
    Language English
    Dates of publication 2018-1001
    Size p. 1066-1073.
    Publishing place Elsevier B.V.
    Document type Article
    ZDB-ID 282732-3
    ISSN 1879-0003 ; 0141-8130
    ISSN (online) 1879-0003
    ISSN 0141-8130
    DOI 10.1016/j.ijbiomac.2018.06.022
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  9. Article: Structure and interaction of Corynebacterium pseudotuberculosis cold shock protein A with Y‐box single‐stranded DNA fragment

    Caruso, Icaro P / Andrew J. Dingley / Dieter Willbold / Marinônio L. Cornélio / Monika A. Coronado / Raghuvir K. Arni / Raphael J. Eberle / Vineet Panwalkar

    FEBS journal. 2018 Jan., v. 285, no. 2

    2018  

    Abstract: Cold shock proteins (Csps) function to preserve cell viability at low temperatures by binding to nucleic acids and consequently control gene expression. The mesophilic bacterium Corynebacterium pseudotuberculosis is the causative agent of caseous ... ...

    Abstract Cold shock proteins (Csps) function to preserve cell viability at low temperatures by binding to nucleic acids and consequently control gene expression. The mesophilic bacterium Corynebacterium pseudotuberculosis is the causative agent of caseous lymphadenitis in animals, and infection in livestock is a considerable economic burden worldwide. In this report, the structure of cold shock protein A from Cp (Cp‐CspA) and biochemical analysis of its temperature‐dependent interaction with a Y‐box ssDNA motif is presented. The Cp‐CspA structure contains five β‐strands making up a β‐barrel fold with 11 hydrophobic core residues and two salt bridges that confers it with a melting temperature of ~ 54 °C that is similar to mesophilic Bs‐CspB. Chemical shift perturbations analysis revealed that residues in the nucleic acid‐binding motifs (RNP 1 and 2) and loop 3 are involved in binding to the Y‐box fragment either by direct interaction or by conformational rearrangements remote from the binding region. Fluorescence quenching experiments of Cp‐CspA showed that the dissociation constants for Y‐box ssDNA binding is nanomolar and the binding affinity decreased as the temperature increased, indicating that the interaction is enthalpically driven and the hydrogen bonds and van der Waals forces are important contributions for complex stabilization. The Y31 of Cp‐CspA is a particular occurrence among Csps from mesophilic bacteria that provide a possible explanation for the higher binding affinity to ssDNA than that observed for Bs‐CspB. Anisotropy measurements indicated that the reduction in molecular mobility of Cp‐CspA upon Y‐box binding is characterized by a cooperative process. DATABASE: Resonance assignment and structural data are available in the Biological Magnetic Resonance Data Bank and Protein Data Bank under accession number 26802 and 5O6F, respectively.
    Keywords bacteria ; binding capacity ; caseous lymphadenitis ; cell viability ; cold shock proteins ; Corynebacterium pseudotuberculosis ; dissociation ; DNA fragmentation ; fluorescence ; gene expression ; hydrogen bonding ; hydrophobicity ; livestock ; magnetism ; melting point ; single-stranded DNA ; temperature ; van der Waals forces
    Language English
    Dates of publication 2018-01
    Size p. 372-390.
    Publishing place John Wiley & Sons, Ltd
    Document type Article
    Note JOURNAL ARTICLE
    ZDB-ID 2173655-8
    ISSN 1742-4658 ; 1742-464X
    ISSN (online) 1742-4658
    ISSN 1742-464X
    DOI 10.1111/febs.14350
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  10. Article: The polyanions heparin and suramin impede binding of free adenine to a DNA glycosylase from C. pseudotuberculosis

    Eberle, Raphael J / Monika A. Coronado / Rafaela S. Peinado / Fabio R. de Moraes / Danilo Olivier / Thiago Dreyer / Debora de Oliveira Lopes / Brenda Silva Rosa da Luz / Vasco Azevedo / Raghuvir K. Arni

    International journal of biological macromolecules. 2019 Mar. 15, v. 125

    2019  

    Abstract: Currently no effective treatment is available to combat infections caused by Corynebacterium pseudotuberculosis in livestock. Survival of this Gram-positive bacterium in rapidly-growing pathogens in hostile environments is strongly dependent on the ... ...

    Abstract Currently no effective treatment is available to combat infections caused by Corynebacterium pseudotuberculosis in livestock. Survival of this Gram-positive bacterium in rapidly-growing pathogens in hostile environments is strongly dependent on the existence of a robust DNA repair system to prevent DNA mutations and contribute to bacterial colonization and virulence. The adenine/guanine-specific DNA glycosylase (MutY) is evolutionarily conserved and has been well characterized due to its central role in the prevention of mutagenesis and DNA repair.The aim of this study was the characterization of the target protein interaction with free adenine, suramin, and heparin, as well as the binding competition characterization between the molecules.The dissociation constant for free adenine interaction with Corynebacterium pseudotuberculosis MutY (Cp-MutY) was determined, 86 ± 2.5 μM. NMR competition experiments demonstrated, that the polyanions heparin and suramin compete with adenine for the protein active site. The determined dissociation constant for the heparin/Cp-MutY interaction was 5.9 ± 1.0 μM and for suramin was 16 ± 1.5 μM. Docking of both polyanions with Cp-MutY revealed a possible mode of interaction and indicates that these molecules can interfere with the protein interaction with damaged DNA or prevent the binding of the adenine base in the enzyme active site.
    Keywords Corynebacterium pseudotuberculosis ; DNA ; DNA repair ; Gram-positive bacteria ; active sites ; adenine ; anions ; bacterial colonization ; dissociation ; enzymes ; heparin ; livestock ; mutagenesis ; nuclear magnetic resonance spectroscopy ; pathogens ; suramin ; virulence
    Language English
    Dates of publication 2019-0315
    Size p. 459-468.
    Publishing place Elsevier B.V.
    Document type Article
    ZDB-ID 282732-3
    ISSN 1879-0003 ; 0141-8130
    ISSN (online) 1879-0003
    ISSN 0141-8130
    DOI 10.1016/j.ijbiomac.2018.12.067
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