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Lindgren, Anders E. G.
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Publications (10 of 12) 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
Ekblad, T., Verheugd, P., Lindgren, A. E., Nyman, T., Elofsson, M. & Schüler, H. (2018). Identification of Poly(ADP-Ribose) Polymerase Macrodomain Inhibitors Using an AlphaScreen Protocol. SLAS DISCOVERY, 23(4), 353-362
Open this publication in new window or tab >>Identification of Poly(ADP-Ribose) Polymerase Macrodomain Inhibitors Using an AlphaScreen Protocol
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2018 (English)In: SLAS DISCOVERY, ISSN 2472-5552, Vol. 23, no 4, p. 353-362Article in journal (Refereed) Published
Abstract [en]

Macrodomains recognize intracellular adenosine diphosphate (ADP)-ribosylation resulting in either removal of the modification or a protein interaction event. Research into compounds that modulate macrodomain functions could make important contributions. We investigated the interactions of all seven individual macrodomains of the human poly(ADP-ribose) polymerase (PARP) family members PARP9, PARP14, and PARP15 with five mono-ADP-ribosylated (automodified) ADP-ribosyltransferase domains using an AlphaScreen assay. Several mono-ADP-ribosylation-dependent interactions were identified, and they were found to be in the micromolar affinity range using surface plasmon resonance (SPR). We then focused on the interaction between PARP14 macrodomain-2 and the mono-ADP-ribosylated PARP10 catalytic domain, and probed a similar to 1500-compound diverse library for inhibitors of this interaction using AlphaScreen. Initial hit compounds were verified by concentration-response experiments using AlphaScreen and SPR, and they were tested against PARP14 macrodomain-2 and -3. Two initial hit compounds and one chemical analog each were further characterized using SPR and microscale thermophoresis. In conclusion, our results reveal novel macrodomain interactions and establish protocols for identification of inhibitors of such interactions.

Place, publisher, year, edition, pages
Sage Publications, 2018
Keywords
ADP-ribosylation, macrodomain inhibitor, PARP, protein-protein interaction, AlphaScreen
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-147337 (URN)10.1177/2472555217750870 (DOI)000429940100005 ()29316839 (PubMedID)
Available from: 2018-05-14 Created: 2018-05-14 Last updated: 2018-06-09Bibliographically approved
Lindgren, A. E. G., Oberg, C. T., Hillgren, J. M. & Elofsson, M. (2016). Total Synthesis of the Resveratrol Oligomers (+/-)-Ampelopsin B and (+/-)-E-Viniferin. European Journal of Organic Chemistry (3), 426-429
Open this publication in new window or tab >>Total Synthesis of the Resveratrol Oligomers (+/-)-Ampelopsin B and (+/-)-E-Viniferin
2016 (English)In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, no 3, p. 426-429Article in journal (Refereed) Published
Abstract [en]

The total synthesis of the resveratrol dimers (+/-)-ampelopsin B and (+/-)-E-viniferin is reported. Highlights of the approach include the use of cyclopropylmethyl groups to protect aromatic alcohols. This group allows an acid promoted three-step, one-pot deprotection-epimerization-cyclization of an advanced intermediate to give (+/-)-ampelopsin B. An important advantage with our strategy is the possibility of synthesizing analogs to these natural products to further study the chemistry and biology of resveratrol oligomers.

Keywords
Protecting groups, Cyclopropylmethyl, Polyphenols, Total synthesis, Natural products
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-116747 (URN)10.1002/ejoc.201501486 (DOI)000368815700002 ()
Available from: 2016-02-19 Created: 2016-02-11 Last updated: 2018-06-07Bibliographically approved
Lindgren, A. (2015). Synthesis of Small Molecules Targeting ADP-Ribosyltransferases and Total Synthesis of Resveratrol Based Natural Products. (Doctoral dissertation). Umeå: Umeå universitet
Open this publication in new window or tab >>Synthesis of Small Molecules Targeting ADP-Ribosyltransferases and Total Synthesis of Resveratrol Based Natural Products
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Diphtheria Toxin-like ADP-Ribosyltransferases

The Human ADP-ribosyl transferases (ARTDs) are a group of poorly studied enzymes which are believed to be involved in e.g. DNA repair, protein degradation, transcription regulation and cell death. Medicinal chemistry programmes aimed at developing selective inhibitors of these ARTDs were initiated. A suitable starting compound for one of these enzymes, ARTD3, was found by screening a library of NAD-mimics using a thermal shift assay. A virtual screening protocol was instead developed in order to find novel inhibitors of ARTD7, 8, and 10. The hit compounds were then further developed into selective inhibitors of the corresponding ARTDs by systematically varying different structural features using a combination of synthetic organic chemistry, computational chemistry and structural biology. Compounds were initially characterized using differential scanning fluorimetry which was later replaced with an enzymatic assay to obtain IC50 values. Biotinylated analogs were also synthesized in an attempt to develop an AlphaScreen assay. A selective ARTD3 inhibitor was ultimately identified and found to delay DNA repair in cells after γ-irradiation. These compounds are potentially valuable tools for elucidating the biological role of the poorly characterized ARTD-family of proteins.

Total Synthesis of Resveratrol Based Natural Products

The polyphenolic natural product (-)-hopeaphenol was found to inhibit the type III secretion system present in certain gram-negative bacteria. (-)-Hopeaphenol is a tetramer of resveratrol and in order to investigate whether the entire structure was essential for inhibition two resveratrol dimers, ε-viniferin and ampelopsin B, were synthesized using a flexible and divergent synthetic route. Highlights of the synthetic strategy include the use of cyclopropylmethyl protecting groups, allowing an acid mediated three-step-one-pot deprotection-epimerization-cyclization of an advanced intermediate to form ampelopsin B. All previously reported syntheses of these two natural products include a dimerization of resveratrol which severly limits the possibilities to synthesize structural analogs. This new strategy enables the synthesis of a wide variety of analogs to ε-viniferin and ampelopsin B.

Abstract [sv]

Populärvetenskaplig sammanfattning

Små molekyler för att identifiera proteiners funktion

Vår arvsmassa innehåller cirka 24000 gener som i sin tur innehåller information för hur de tusentals proteiner vi är uppbyggda av ska framställas. Många läkemedel fungerar genom att en molekyl interagerar med ett av dessa proteiner och hämmar dess funktion för att på så sätt framkalla en önskad effekt. Vi vet dock inte vilken funktion många av våra proteiner fyller vilket ofta gör utvecklingen av nya läkemedel svår eller omöjlig. Den första delen av denna avhandling beskriver en grupp proteiner kallade ARTDs och hur små molekyler kan framställas och systematiskt förbättras för att till slut helt kunna slå ut vissa av dessa ARTDs. Genom att sedan studera vilka effekter detta medför kan man ta reda på vilken funktion proteinet fyller. På längre sikt skulle denna kunskap sedan kunna användas för att utveckla nya läkemedel genom att till exempel slå ut de proteiner som orsakar en sjukdom.

Totalsyntes av naturprodukter

Naturprodukter defineras inom kemin som naturligt förekommande molekyler som produceras av levande organismer. De kan hittas i allt från mikroorganismer och växter till djur och kan vara en del av deras ämnesomsättning, en restprodukt eller ha någon annan funktion, känd eller okänd. Människor, och i vissa fall även andra djur, har sedan urminnes tider ovetandes använt dessa molekyler för en mängd olika syften, som gifter, färgämnen eller läkemedel. Penicillin är en av de mest kända, men mer än hälften av de nya läkemedel som godkänts de senaste trettio åren bygger på naturprodukter eller har inspirerats av dessa. De fortsätter således att vara viktiga för utvecklingen av nya läkemedel trots att vi idag har möjligheten att utveckla sådana från grunden.

Att framställa naturprodukter på konstgjord väg kallas totalsyntes och är ofta en mycket svår och tidskrävande process. Vanligtvis rör det sig om mycket stora och komplexa molekyler och det finns sällan ett uppenbart sätt att genomföra totalsyntesen. För att bättre klara av detta måste nya metoder utvecklas. Den andra delen av denna avhandling beskriver nya metoder för att framställa komplexa molekyler kallade polyfenoler. Målet var att dessa metoder skulle vara så pass flexibla att de även kan användas för att framställa nya polyfenoler som aldrig tidigare existerat men som har förbättrade egenskaper.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2015. p. 115
Keywords
organic synthesis, quinazolinone, ARTD, PARP, total synthesis, polyphenols, bensofuranes
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-108010 (URN)978-91-7601-329-8 (ISBN)
Public defence
2015-10-02, KBC-huset, KB3A9 (lilla hörsalen i KBC-huset), Umeå universitet, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2015-09-11 Created: 2015-09-01 Last updated: 2018-06-07Bibliographically approved
Ekblad, T., Lindgren, A. E. G., Andersson, C. D., Caraballo, R., Thorsell, A.-G., Karlberg, T., . . . Elofsson, M. (2015). Towards small molecule inhibitors of mono-ADP-ribosyltransferases. European Journal of Medicinal Chemistry, 95, 546-551
Open this publication in new window or tab >>Towards small molecule inhibitors of mono-ADP-ribosyltransferases
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2015 (English)In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 95, p. 546-551Article in journal (Refereed) Published
Abstract [en]

Protein ADP-ribosylation is a post-translational modification involved in DNA repair, protein degradation, transcription regulation, and epigenetic events. Intracellular ADP-ribosylation is catalyzed predominantly by ADP-ribosyltransferases with diphtheria toxin homology (ARTDs). The most prominent member of the ARTD family, poly(ADP-ribose) polymerase-1 (ARTD1/PARP1) has been a target for cancer drug development for decades. Current PARP inhibitors are generally non-selective, and inhibit the mono-ADP-ribosyltransferases with low potency. Here we describe the synthesis of acylated amino benzamides and screening against the mono-ADP-ribosyltransferases ARTD7/PARP15, ARTD8/PARP14, ARTD10/PARP10, and the poly-ADP-ribosyltransferase ARTD1/PARP1. The most potent compound inhibits ARTD10 with sub-micromolar IC50.

Keywords
Mono-ADP-ribosyltransferase, mART, Poly(ADP-ribose) polymerase, Diphtheria toxin-like ADP-ribosyltransferase, ARTD inhibitor, PARP inhibitor
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-106136 (URN)10.1016/j.ejmech.2015.03.067 (DOI)000354139900046 ()25847771 (PubMedID)
Funder
Swedish Research Council, 2012-5247Swedish Foundation for Strategic Research , RBc08-0014
Available from: 2015-07-13 Created: 2015-07-09 Last updated: 2018-06-07Bibliographically approved
Marwaha, S., Uvell, H., Salin, O., Lindgren, A. E. G., Silver, J., Elofsson, M. & Gylfe, Å. (2014). N-acylated derivatives of sulfamethoxazole and sulfafurazole inhibit intracellular growth of Chlamydia trachomatis. Antimicrobial Agents and Chemotherapy, 58(5), 2968-2971
Open this publication in new window or tab >>N-acylated derivatives of sulfamethoxazole and sulfafurazole inhibit intracellular growth of Chlamydia trachomatis
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2014 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 58, no 5, p. 2968-2971Article in journal (Refereed) Published
Abstract [en]

Antibacterial compounds with novel modes of action are needed for management of bacterial infections. Here we describe a high-content screen of 9,800 compounds identifying acylated sulfonamides as novel growth inhibitors of the sexually transmitted pathogen Chlamydia trachomatis. The effect was bactericidal and distinct from that of sulfonamide antibiotics, as para-aminobenzoic acid did not reduce efficacy. Chemical inhibitors play an important role in Chlamydia research as probes of potential targets and as drug development starting points.

Place, publisher, year, edition, pages
American Society for Microbiology, 2014
National Category
Pharmaceutical Sciences Pharmacology and Toxicology Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-89208 (URN)10.1128/AAC.02015-13 (DOI)000334364300064 ()
Available from: 2014-05-28 Created: 2014-05-26 Last updated: 2018-06-07Bibliographically approved
Lindgren, A. E., Larsson, A., Linusson, A. & Elofsson, M. (2014). Statistical molecular design: a tool to follow up hits from small-molecule screening.. Methods in Molecular Biology, 1056, 169-188
Open this publication in new window or tab >>Statistical molecular design: a tool to follow up hits from small-molecule screening.
2014 (English)In: Methods in Molecular Biology, ISSN 1064-3745, E-ISSN 1940-6029, Vol. 1056, p. 169-188Article in journal (Refereed) Published
Abstract [en]

In high-throughput screening (HTS) a robust assay is used to interrogate a large collection of small organic molecules in order to find compounds, hits, with a desired biological activity. The hits are then further explored by an iterative process where new compounds are designed, purchased, or synthesized, followed by an evaluation in one or more assays. Statistical molecular design (SMD) is a useful method to select a balanced, varied, and information-rich compound collection based on hits from HTS in order to create a foundation for development of optimized compounds with improved properties. In this chapter, we describe the use of SMD to explore a hit obtained from small-molecule screening.

Place, publisher, year, edition, pages
Springer, 2014
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-85440 (URN)10.1007/978-1-62703-592-7_17 (DOI)24306873 (PubMedID)
Available from: 2014-02-04 Created: 2014-02-04 Last updated: 2018-06-08Bibliographically approved
Lindgren, A. E. G., Karlberg, T., Ekblad, T., Spjut, S., Thorsell, A.-G., Andersson, C. D., . . . Elofsson, M. (2013). Chemical Probes to Study ADP-Ribosylation: Synthesis and Biochemical Evaluation of Inhibitors of the Human ADP-Ribosyltransferase ARTD3/PARP3. Journal of Medicinal Chemistry, 56(23), 9556-9568
Open this publication in new window or tab >>Chemical Probes to Study ADP-Ribosylation: Synthesis and Biochemical Evaluation of Inhibitors of the Human ADP-Ribosyltransferase ARTD3/PARP3
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2013 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 56, no 23, p. 9556-9568Article in journal (Refereed) Published
Abstract [en]

The racemic 3-(4-oxo-3,4-dihydroquinazolin-2-yl)-N-[1-(pyridin-2-yl)ethyl]propanamide, 1, has previously been identified as a potent but unselective inhibitor of diphtheria toxin-like ADP-ribosyltransferase 3 (ARTD3). Herein we describe synthesis and evaluation of SS compounds in this class. It was found that the stereochemistry is of great importance for both selectivity and potency and that substituents on the phenyl ring resulted in poor solubility. Certain variations at the meso position were tolerated and caused a large shift in the binding pose. Changes to the ethylene linker that connects the quinazolinone to the amide were also investigated but proved detrimental to binding. By combination of synthetic organic chemistry and structure-based design, two selective inhibitors of ARTD3 were discovered.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2013
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-84774 (URN)10.1021/jm401394u (DOI)000328529700015 ()
Available from: 2014-01-29 Created: 2014-01-20 Last updated: 2018-06-08Bibliographically approved
Andersson, E. K., Bengtsson, C., Evans, M. L., Chorell, E., Sellstedt, M., Lindgren, A. E. .., . . . Chapman, M. R. (2013). Modulation of Curli Assembly and Pellicle Biofilm Formation by Chemical and Protein Chaperones. Chemistry and Biology, 20(10), 1245-1254
Open this publication in new window or tab >>Modulation of Curli Assembly and Pellicle Biofilm Formation by Chemical and Protein Chaperones
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2013 (English)In: Chemistry and Biology, ISSN 1074-5521, E-ISSN 1879-1301, Vol. 20, no 10, p. 1245-1254Article in journal (Refereed) Published
Abstract [en]

Enteric bacteria assemble functional amyloid fibers, curli, on their surfaces that share structural and biochemical properties with disease-associated amyloids. Here, we test rationally designed 2-pyridone compounds for their ability to alter amyloid formation of the major curli subunit CsgA. We identified several compounds that discourage CsgA amyloid formation and several compounds that accelerate CsgA amyloid formation. The ability of inhibitor compounds to stop growing CsgA fibers was compared to the same property of the CsgA chaperone, CsgE. CsgE blocked CsgA amyloid assembly and arrested polymerization when added to actively polymerizing fibers. Additionally, CsgE and the 2-pyridone inhibitors prevented biofilm formation by Escherichia coli at the air-liquid interface of a static culture. We demonstrate that curli amyloid assembly and curli-dependent biofilm formation can be modulated not only by protein chaperones, but also by "chemical chaperones."

Place, publisher, year, edition, pages
Elsevier, 2013
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-82340 (URN)10.1016/j.chembiol.2013.07.017 (DOI)000326429400010 ()24035282 (PubMedID)
Funder
Swedish Research Council, 2011-6259, 2010-4730
Available from: 2013-10-30 Created: 2013-10-30 Last updated: 2018-06-08Bibliographically approved
Lindgren, A. E. G., Karlberg, T., Thorsell, A.-G., Hesse, M., Spjut, S., Ekblad, T., . . . Schueler, H. (2013). PARP Inhibitor with Selectivity Toward ADP-Ribosyltransferase ARTD3/PARP3. ACS Chemical Biology, 8(8), 1698-1703
Open this publication in new window or tab >>PARP Inhibitor with Selectivity Toward ADP-Ribosyltransferase ARTD3/PARP3
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2013 (English)In: ACS Chemical Biology, ISSN 1554-8929, E-ISSN 1554-8937, Vol. 8, no 8, p. 1698-1703Article in journal (Refereed) Published
Abstract [en]

Inhibiting ADP-ribosyl transferases with PARP-inhibitors is considered a promising strategy for the treatment of many cancers and ischemia, but most of the cellular targets are poorly characterized. Here, we describe an inhibitor of ADP-ribosyltransferase-3/poly(ADP-ribose) polymerase-3 (ARTD3), a regulator of DNA repair and mitotic progression. In vitro profiling against 12, members of the enzyme family suggests selectivity for ARTD3, and crystal structures illustrate the molecular basis for inhibitor selectivity. The compound is active in cells, where it elicits ARTD3-specific effects at submicromolar concentration. Our results show that by targeting the nicotinamide binding site, selective inhibition can be achieved among the closest relatives of the validated clinical target, ADP-ribosyltransferase-1/poly(ADP-ribose) polymerase-1.

National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-81013 (URN)10.1021/cb4002014 (DOI)000323363000008 ()
Available from: 2013-09-30 Created: 2013-09-30 Last updated: 2018-06-08Bibliographically approved
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