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Chorell, Erik
Publications (10 of 38) Show all publications
Flentie, K., Harrison, G. A., Tükenmez, H., Livny, J., Good, J. A. D., Sarkar, S., . . . Stallings, C. L. (2019). Chemical disarming of isoniazid resistance in Mycobacterium tuberculosis. Proceedings of the National Academy of Sciences of the United States of America, 116(21), 10510-10517
Open this publication in new window or tab >>Chemical disarming of isoniazid resistance in Mycobacterium tuberculosis
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2019 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, no 21, p. 10510-10517Article in journal (Refereed) Published
Abstract [en]

Mycobacterium tuberculosis (Mtb) killed more people in 2017 than any other single infectious agent. This dangerous pathogen is able to withstand stresses imposed by the immune system and tolerate exposure to antibiotics, resulting in persistent infection. The global tuberculosis (TB) epidemic has been exacerbated by the emergence of mutant strains of Mtb that are resistant to frontline antibiotics. Thus, both phenotypic drug tolerance and genetic drug resistance are major obstacles to successful TB therapy. Using a chemical approach to identify compounds that block stress and drug tolerance, as opposed to traditional screens for compounds that kill Mtb, we identified a small molecule, C10, that blocks tolerance to oxidative stress, acid stress, and the frontline antibiotic isoniazid (INH). In addition, we found that C10 prevents the selection for INH-resistant mutants and restores INH sensitivity in otherwise INH-resistant Mtb strains harboring mutations in the katG gene, which encodes the enzyme that converts the prodrug INH to its active form. Through mechanistic studies, we discovered that C10 inhibits Mtb respiration, revealing a link between respiration homeostasis and INH sensitivity. Therefore, by using C10 to dissect Mtb persistence, we discovered that INH resistance is not absolute and can be reversed.

Place, publisher, year, edition, pages
The National Academy of Scionces of the United States of America, 2019
Keywords
Mycobacterium tuberculosis, drug tolerance, antibiotic resistance, isoniazid, respiration
National Category
Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-159857 (URN)10.1073/pnas.1818009116 (DOI)000468403400054 ()31061116 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationSwedish Foundation for Strategic Research The Kempe FoundationsNIH (National Institute of Health)
Available from: 2019-06-10 Created: 2019-06-10 Last updated: 2019-06-10Bibliographically approved
Prasad, B., Jamroskovic, J., Bhowmik, S., Kumar, R., Romell, T., Sabouri, N. & Chorell, E. (2018). Flexible Versus Rigid G-Quadruplex DNA Ligands: Synthesis of Two Series of Bis-indole Derivatives and Comparison of Their Interactions with G-Quadruplex DNA. Chemistry - A European Journal, 24(31), 7926-7938
Open this publication in new window or tab >>Flexible Versus Rigid G-Quadruplex DNA Ligands: Synthesis of Two Series of Bis-indole Derivatives and Comparison of Their Interactions with G-Quadruplex DNA
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2018 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 24, no 31, p. 7926-7938Article in journal (Refereed) Published
Abstract [en]

Small molecules that target G-quadruplex (G4) DNA structures are not only valuable to study G4 biology but also for their potential as therapeutics. This work centers around how different design features of small molecules can affect the interactions with G4 DNA structures, exemplified by the development of synthetic methods to bis-indole scaffolds. Our synthesized series of bis-indole scaffolds are structurally very similar but differ greatly in the flexibility of their core structures. The flexibility of the molecules proved to be an advantage compared to locking the compounds in the presumed bioactive G4 conformation. The flexible derivatives demonstrated similar or even improved G4 binding and stabilization in several orthogonal assays even though their entropic penalty of binding is higher. In addition, molecular dynamics simulations with the c-MYC G4 structure showed that the flexible compounds adapt better to the surrounding. This was reflected by an increased number of both stacking and polar interactions with both the residues in the G4 DNA structure and the DNA residues just upstream of the G4 structure.

Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2018
Keywords
DNA structures, G-quadruplexes, bis-indoles, drug design, nitrogen heterocycles
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-148052 (URN)10.1002/chem.201800078 (DOI)000434216600019 ()29603472 (PubMedID)2-s2.0-85048327004 (Scopus ID)
Available from: 2018-06-14 Created: 2018-06-14 Last updated: 2018-11-01Bibliographically approved
Bhattacharjee, S., Chakraborty, S., Chorell, E., Sengupta, P. K. & Bhowmik, S. (2018). Importance of the hydroxyl substituents in the B-ring of plant flavonols on their preferential binding interactions with VEGF G-quadruplex DNA: Multi-spectroscopic and molecular modeling studies. International Journal of Biological Macromolecules, 118, 629-639
Open this publication in new window or tab >>Importance of the hydroxyl substituents in the B-ring of plant flavonols on their preferential binding interactions with VEGF G-quadruplex DNA: Multi-spectroscopic and molecular modeling studies
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2018 (English)In: International Journal of Biological Macromolecules, ISSN 0141-8130, E-ISSN 1879-0003, Vol. 118, p. 629-639Article in journal (Refereed) Published
Abstract [en]

G-quadruplex (G4) structures are known to be promising anticancer drug targets and flavonols (an important class of fiavonoids) are small molecules reported to possess several health-promoting properties including those of anticancer activities. In this work, we explored the interactions of the structurally related plant flavonols kaempferol (KAE; 3,5,7,4'-OH flavone) and morin (MOR; 3,5,7,2',4'-OH flavone) with various G4-DNA sequences along with duplex DNA using a combination of spectroscopic and molecular docking studies. Our results revealed that KAE shows preferential interaction with VEGF G4-DNA in comparison to the other G4 sequences and duplex DNA. Moreover, KAE enhances the thermal stability of VEGF G4-DNA. In contrast, MOR exhibits an appreciably weaker level of interaction with both duplex and various G4-DNAs, with no significant structural specificity. The contrasting DNA binding behaviors suggest a crucial role of the 2'-OH substituent in the Bring of flavonol moiety. While KAE is relatively planar, MOR adopts a significantly non-planar conformation attributable to steric hindrance from the additional 2'-OH substituent. This small structural difference is apparently very important for the ability of KAE and MOR to interact with VEGF G4-DNA. Thus, KAE (but not MOR) appears to be an effective ligand for VEGF G4-DNA, opening up possibilities of its application for regulation of gene expression in cancer cells. 

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
VEGF G-quadruplex DNA, Kaempferol, Morin, Spectroscopy, Molecular docking, Preferential binding
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-152378 (URN)10.1016/j.ijbiomac.2018.06.115 (DOI)000445170200071 ()29953891 (PubMedID)
Funder
The Kempe Foundations, SMK-1632.2
Note

Part: A

Available from: 2018-10-05 Created: 2018-10-05 Last updated: 2018-10-05Bibliographically approved
Pokrzywa, M., Pawelek, K., Kucia, W. E., Sarbak, S., Chorell, E., Almqvist, F. & Wittung-Stafshede, P. (2017). Effects of small-molecule amyloid modulators on a Drosophila model of Parkinson's disease. PLoS ONE, 12(9), Article ID e0184117.
Open this publication in new window or tab >>Effects of small-molecule amyloid modulators on a Drosophila model of Parkinson's disease
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2017 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 9, article id e0184117Article in journal (Refereed) Published
Abstract [en]

Alpha-synuclein (aS) amyloid formation is involved in Parkinson's disease (PD); therefore, small molecules that target aS and affect its aggregation are of interest as future drug candidates. We recently reported modified ring-fused 2-pyridones that modulate aS amyloid formation in vitro. Here, we describe the effects of such molecules on behavioral parameters of a Drosophila model of PD (i.e., flies expressing human aS), using a new approach (implemented in a commercially available FlyTracker system) to quantify fly mobility. FlyTracker allows for automated analysis of walking and climbing locomotor behavior, as it collects large sequences of data over time in an unbiased manner. We found that the molecules per se have no toxic or kinetic effects on normal flies. Feeding aS-expressing flies with the amyloid-promoting molecule FN075, remarkably, resulted in increased fly mobility at early time points; however, this effect switched to reduced mobility at later time points, and flies had shorter life spans than controls. In contrast, an amyloid inhibitor increased both fly kinetics and life span. In agreement with increased aS amyloid formation, the FN075-fed flies had less soluble aS, and in vitro aS-FN075 interactions stimulated aS amyloid formation. In addition to a new quantitative approach to probe mobility (available in FlyTracker), our results imply that aS regulates brain activity such that initial removal (here, by FN075-triggered assembly of aS) allows for increased fly mobility.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:umu:diva-139797 (URN)10.1371/journal.pone.0184117 (DOI)000408816900026 ()28863169 (PubMedID)
Available from: 2017-09-27 Created: 2017-09-27 Last updated: 2018-06-09Bibliographically approved
Livendahl, M., Jamroskovic, J., Hedenström, M., Görlich, T., Sabouri, N. & Chorell, E. (2017). Synthesis of phenanthridine spiropyrans and studies of their effects on G-quadruplex DNA. Organic and biomolecular chemistry, 15(15), 3265-3275
Open this publication in new window or tab >>Synthesis of phenanthridine spiropyrans and studies of their effects on G-quadruplex DNA
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2017 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 15, no 15, p. 3265-3275Article in journal (Refereed) Published
Abstract [en]

G-quadruplex (G4) DNA structures are involved in many important biological processes and can be linked to several human diseases. Drug-like low molecular weight compounds that target G4 structures are therefore interesting not only for their potential therapeutic properties but also for their potential use as chemical research tools. We report here on the development of methods to synthesize spiropyrans using a condensation-cyclisation reaction of quaternary salts of [small alpha]-methyl quinoline or phenanthridine with salicylaldehydes. Evaluation of the synthesized phenanthridine spiropyrans' interactions with G4 DNA was performed with a Thioflavin T displacement assay, circular dichroism, Taq DNA polymerase stop assay, and NMR. This revealed that the substitution pattern on the phenanthridine spiropyrans was very important for their ability to bind and stabilize G4 structures. Some of the synthesized low molecular weight spirocyclic compounds efficiently stabilized G4 structures without inducing structural changes by binding the first G-tetrad in the G4 structure.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2017
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-134560 (URN)10.1039/C7OB00300E (DOI)000399201000022 ()28349141 (PubMedID)
Available from: 2017-05-09 Created: 2017-05-09 Last updated: 2018-06-09Bibliographically approved
Kumar, V., Chand, K. & Chorell, E. (2017). Synthesis of Various N-Substituted 4-Aryloxy/Thiophenoxy/Thioisopropyloxy-Phthalimides. ChemistrySelect, 2(11), 3293-3296
Open this publication in new window or tab >>Synthesis of Various N-Substituted 4-Aryloxy/Thiophenoxy/Thioisopropyloxy-Phthalimides
2017 (English)In: ChemistrySelect, ISSN 2365-6549, Vol. 2, no 11, p. 3293-3296Article in journal (Refereed) Published
Abstract [en]

N-substituted phthalimides have been used to target many biological systems with examples that are clinically used as drugs. Furthermore, N-substituted phthalimides can also be used in other settings such as in the preparation of polymers, as catalysts, and as protective groups. Because of all these important fields of application, the synthesis of phthalimides is well reported. However, synthetic methods to phthalimides with different heteroatom substituents in position 4 are lacking. The present work describes the development of robust synthetic methods to N-substituted 4-aryloxy/thiophenoxy/thioisopropyloxy-phthalimides. The developed methods allow for the introduction of these substituents through an atom efficient one-step synthesis, which gives good to excellent yields and tolerate a wide range of substituents.

Place, publisher, year, edition, pages
John Wiley & Sons, 2017
Keywords
Green synthesis, Methodology and Reactions, Microwave synthesis, Nucleophilic substitution, Phthalimide
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-134548 (URN)10.1002/slct.201700721 (DOI)000399332800013 ()
Available from: 2017-05-08 Created: 2017-05-08 Last updated: 2018-06-09Bibliographically approved
Good, J. A. D., Andersson, C., Hansen, S., Wall, J., Krishnan, S., Begum, A., . . . Johansson, J. (2016). Attenuating Listeria monocytogenes virulence by targeting the regulatory protein PrfA. Cell chemical biology, 23(3), 404-414
Open this publication in new window or tab >>Attenuating Listeria monocytogenes virulence by targeting the regulatory protein PrfA
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2016 (English)In: Cell chemical biology, ISSN 2451-9448, Vol. 23, no 3, p. 404-414Article in journal (Refereed) Published
Abstract [en]

The transcriptional activator PrfA, a member of the Crp/Fnr family, controls the expression of some key virulence factors necessary for infection by the human bacterial pathogen Listeria monocytogenes. Phenotypic screening identified ring-fused 2-pyridone molecules that at low micromolar concentrations attenuate L. monocytogenes infectivity by reducing the expression of virulence genes, without compromising bacterial growth. These inhibitors bind the transcriptional regulator PrfA and decrease its affinity for the consensus DNA binding site. Structural characterization of this interaction revealed that one of the ring-fused 2-pyridones, compound 1, binds within a hydrophobic pocket, located between the C- and N-terminal domains of PrfA, and interacts with residues important for PrfA activation. This indicates that these inhibitors maintain the DNA-binding helix-turn-helix motif of PrfA in a disordered state, thereby preventing a PrfA:DNA interaction. Ring-fused 2-pyridones represent a new class of chemical probes for studying virulence in L. monocytogenes.

National Category
Biochemistry and Molecular Biology
Research subject
Molecular Biology
Identifiers
urn:nbn:se:umu:diva-114083 (URN)10.1016/j.chembiol.2016.02.013 (DOI)000381508300013 ()26991105 (PubMedID)
Note

Originally published in manuscipt form in thesis.

Available from: 2016-01-12 Created: 2016-01-12 Last updated: 2018-06-07Bibliographically approved
Livendahl, M., Jamroskovic, J., Ivanova, S., Demirel, P., Sabouri, N. & Chorell, E. (2016). Design and Synthesis of 2,2'-Diindolylmethanes to Selectively Target Certain G-Quadruplex DNA Structures. Chemistry - A European Journal, 22(37), 13004-13009
Open this publication in new window or tab >>Design and Synthesis of 2,2'-Diindolylmethanes to Selectively Target Certain G-Quadruplex DNA Structures
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2016 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 22, no 37, p. 13004-13009Article in journal (Refereed) Published
Abstract [en]

G-quadruplex (G4) structures carry vital biological functions, and compounds that selectively target certain G4 structures have both therapeutic potential and value as research tools. Along this line, 2,2'-diindolylmethanes have been designed and synthesized in this work based on the condensation of 3,6- or 3,7-disubstituted indoles with aldehydes. The developed class of compounds efficiently stabilizes G4 structures without inducing conformational changes in such structures. Furthermore, the 2,2'-diindolylmethanes target certain G4 structures more efficiently than others and this G4 selectivity can be altered by chemical modifications of the compounds.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-124638 (URN)10.1002/chem.201602416 (DOI)000383763200005 ()27431593 (PubMedID)
Available from: 2016-08-18 Created: 2016-08-18 Last updated: 2018-06-07Bibliographically approved
Jamroskovic, J., Livendahl, M., Eriksson, J., Chorell, E. & Sabouri, N. (2016). Identification of Compounds that Selectively Stabilize Specific G-Quadruplex Structures by Using a Thioflavin T-Displacement Assay as a Tool. Chemistry - A European Journal, 22(52), 18932-18943
Open this publication in new window or tab >>Identification of Compounds that Selectively Stabilize Specific G-Quadruplex Structures by Using a Thioflavin T-Displacement Assay as a Tool
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2016 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 22, no 52, p. 18932-18943Article in journal (Refereed) Published
Abstract [en]

Small molecules are used in the G-quadruplex (G4) research field in vivo and in vitro, and there are increasing demands for ligands that selectively stabilize different G4 structures. Thioflavin T (ThT) emits an enhanced fluorescence signal when binding to G4 structures. Herein, we show that ThT can be competitively displaced by the binding of small molecules to G4 structures and develop a ThT-displacement high-throughput screening assay to find novel and selective G4-binding compounds. We screened approximately 28 000 compounds by using three different G4 structures and identified eight novel G4 binders. Analysis of the structural conformation and stability of the G4 structures in presence of these compounds demonstrated that the four compounds enhance the thermal stabilization of the structures without affecting their structural conformation. In addition, all four compounds also increased the G4-structure block of DNA synthesis by Taq DNA polymerase. Also, two of these compounds showed selectivity between certain Schizosaccharomyces pombe G4 structures, thus suggesting that these compounds or their analogues can be used as selective tools for G4 DNA studies.

Keywords
dyes, DNA structures, dyes, G-quadruplexes, high-throughput screening, nucleobases
National Category
Biochemistry and Molecular Biology Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-128197 (URN)10.1002/chem.201603463 (DOI)000393219300041 ()27862378 (PubMedID)2-s2.0-85002848668 (Scopus ID)
Available from: 2016-11-28 Created: 2016-11-28 Last updated: 2018-06-09Bibliographically approved
Engström, P., Krishnan, K. S., Ngyuen, B. D., Chorell, E., Normark, J., Silver, J., . . . Bergström, S. (2015). A 2-Pyridone-Amide Inhibitor Targets the Glucose Metabolism Pathway of Chlamydia trachomatis. mBio, 6(1), Article ID e02304-14.
Open this publication in new window or tab >>A 2-Pyridone-Amide Inhibitor Targets the Glucose Metabolism Pathway of Chlamydia trachomatis
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2015 (English)In: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 6, no 1, article id e02304-14Article in journal (Refereed) Published
Abstract [en]

In a screen for compounds that inhibit infectivity of the obligate intracellular pathogen Chlamydia trachomatis, we identified the 2-pyridone amide KSK120. A fluorescent KSK120 analogue was synthesized and observed to be associated with the C. trachomatis surface, suggesting that its target is bacterial. We isolated KSK120-resistant strains and determined that several resistance mutations are in genes that affect the uptake and use of glucose-6-phosphate (G-6P). Consistent with an effect on G-6P metabolism, treatment with KSK120 blocked glycogen accumulation. Interestingly, KSK120 did not affect Escherichia coli or the host cell. Thus, 2-pyridone amides may represent a class of drugs that can specifically inhibit C. trachomatis infection. IMPORTANCE Chlamydia trachomatis is a bacterial pathogen of humans that causes a common sexually transmitted disease as well as eye infections. It grows only inside cells of its host organism, within a parasitophorous vacuole termed the inclusion. Little is known, however, about what bacterial components and processes are important for C. trachomatis cellular infectivity. Here, by using a visual screen for compounds that affect bacterial distribution within the chlamydial inclusion, we identified the inhibitor KSK120. As hypothesized, the altered bacterial distribution induced by KSK120 correlated with a block in C. trachomatis infectivity. Our data suggest that the compound targets the glucose-6-phosphate (G-6P) metabolism pathway of C. trachomatis, supporting previous indications that G-6P metabolism is critical for C. trachomatis infectivity. Thus, KSK120 may be a useful tool to study chlamydial glucose metabolism and has the potential to be used in the treatment of C. trachomatis infections.

National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-102254 (URN)10.1128/mBio.02304-14 (DOI)000350631900021 ()25550323 (PubMedID)
Available from: 2015-04-22 Created: 2015-04-22 Last updated: 2018-06-07Bibliographically approved
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