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Lindgren, Cecilia
Publications (10 of 21) Show all publications
Abrahamsson, A., Berner, A., Golebiewska-Pikula, J., Chaudhari, N., Keskitalo, E., Lindgren, C., . . . Chorell, E. (2025). Linker design principles for the precision targeting of oncogenic G-quadruplex DNA with G4-ligand-conjugated oligonucleotides. Bioconjugate chemistry, 36(4), 724-736
Open this publication in new window or tab >>Linker design principles for the precision targeting of oncogenic G-quadruplex DNA with G4-ligand-conjugated oligonucleotides
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2025 (English)In: Bioconjugate chemistry, ISSN 1043-1802, E-ISSN 1520-4812, Vol. 36, no 4, p. 724-736Article in journal (Refereed) Published
Abstract [en]

G-quadruplex (G4) DNA structures are noncanonical secondary structures found in key regulatory regions of the genome, including oncogenic promoters and telomeres. Small molecules, known as G4 ligands, capable of stabilizing G4s hold promise as chemical probes and therapeutic agents. Nevertheless, achieving precise specificity for individual G4 structures within the human genome remains a significant challenge. To address this, we expand upon G4-ligand-conjugated oligonucleotides (GL-Os), a modular platform combining the stabilizing properties of G4-ligands with the sequence specificity of guide DNA oligonucleotides. Central to this strategy is the linker that bridges the G4 ligand and the guide oligonucleotide. In this study, we develop multiple conjugation strategies for the GL-Os that enabled a systematic investigation of the linker in both chemical composition and length, enabling a thorough assessment of their impact on targeting oncogenic G4 DNA. Biophysical, biochemical, and computational evaluations revealed GL-Os with optimized linkers that exhibited enhanced binding to target G4s, even under thermal or structural stress. Notably, longer linkers broadened the range of targetable sequences without introducing steric hindrance, thereby enhancing the platform’s applicability across diverse genomic contexts. These findings establish GL-Os as a robust and versatile tool for the selective targeting of individual G4s. By facilitating precise investigations of G4 biology, this work provides a foundation for advancing G4-targeted therapeutic strategies and exploring their role in disease contexts.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2025
National Category
Biochemistry
Identifiers
urn:nbn:se:umu:diva-237287 (URN)10.1021/acs.bioconjchem.5c00008 (DOI)001448909600001 ()40112195 (PubMedID)2-s2.0-105000394779 (Scopus ID)
Funder
Swedish Research Council, VR-MH 2023-02160Swedish Research Council, VR-NT 2021-04805The Kempe Foundations, JCK-3159The Kempe Foundations, SMK21-0059Knut and Alice Wallenberg FoundationSwedish Cancer Society, 23 2793 PjSwedish Research Council, VR-MH 2023-02160Swedish Research Council, VR-NT 2021-04805The Kempe Foundations, JCK-3159The Kempe Foundations, SMK21-0059Knut and Alice Wallenberg FoundationSwedish Cancer Society, 23 2793 Pj
Available from: 2025-04-07 Created: 2025-04-07 Last updated: 2025-05-28Bibliographically approved
Hainzl, T., Scortti, M., Lindgren, C., Grundström, C., Krypotou, E., Vázquez-Boland, J. A. & Sauer-Eriksson, A. E. (2025). Structural basis of promiscuous inhibition of Listeria virulence activator PrfA by oligopeptides. Cell Reports, 44(2), Article ID 115290.
Open this publication in new window or tab >>Structural basis of promiscuous inhibition of Listeria virulence activator PrfA by oligopeptides
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2025 (English)In: Cell Reports, ISSN 2639-1856, E-ISSN 2211-1247, Vol. 44, no 2, article id 115290Article in journal (Refereed) Published
Abstract [en]

The facultative pathogen Listeria monocytogenes uses a master regulator, PrfA, to tightly control the fitness-costly expression of its virulence factors. We found that PrfA activity is repressed via competitive occupancy of the binding site for the PrfA-activating cofactor, glutathione, by exogenous nutritional oligopeptides. The inhibitory peptides show different sequence and physicochemical properties, but how such a wide variety of oligopeptides can bind PrfA was unclear. Using crystal structure analysis of PrfA complexed with inhibitory tri- and tetrapeptides, we show here that the binding promiscuity is due to the ability of PrfA β5 in the glutathione-binding inter-domain tunnel to establish parallel or antiparallel β sheet-like interactions with the peptide backbone. Spacious tunnel pockets provide additional flexibility for unspecific peptide accommodation while providing selectivity for hydrophobic residues. Hydrophobic contributions from two adjacent peptide residues appear to be critical for efficient PrfA inhibitory binding. In contrast to glutathione, peptide binding prevents the conformational change required for the correct positioning of the DNA-binding helix-turn-helix motifs of PrfA, effectively inhibiting virulence gene expression.

Place, publisher, year, edition, pages
Elsevier, 2025
Keywords
CP: Microbiology, crystal structures of PrfA in complex with oligopeptides, Listeria pathogenesis, Listeria virulence regulation, non-specific oligopeptide-protein binding, oligopeptide-mediated PrfA regulation, peptide-glutathione competitive binding to PrfA, peptide-mediated transcription factor regulation, PrfA allosteric control, PrfA-peptide 3D structure analysis, promiscuous PrfA inhibition by oligopeptides
National Category
Biochemistry Molecular Biology
Identifiers
urn:nbn:se:umu:diva-235844 (URN)10.1016/j.celrep.2025.115290 (DOI)001428945700001 ()2-s2.0-85217797793 (Scopus ID)
Funder
Swedish Research Council, 2015-03607Swedish Research Council, 2019-03771Swedish Research Council, 2018-07152The Kempe FoundationsFamiljen Erling-Perssons StiftelseVinnova, 2018-04969Swedish Research Council Formas, 2019-02496
Available from: 2025-02-25 Created: 2025-02-25 Last updated: 2025-04-24Bibliographically approved
Romero-Castillo, L., Pandey, R. K., Xu, B., Beusch, C. M., Oliveira-Coelho, A., Zeqiraj, K., . . . Holmdahl, R. (2025). Tolerogenic antigen-specific vaccine induces VISTA-enriched regulatory T cells and protects against arthritis in DRB1∗04:01 mice. Molecular Therapy
Open this publication in new window or tab >>Tolerogenic antigen-specific vaccine induces VISTA-enriched regulatory T cells and protects against arthritis in DRB1∗04:01 mice
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2025 (English)In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024Article in journal (Refereed) Epub ahead of print
Abstract [en]

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation, cartilage damage, and bone erosion. Despite improvements with the introduction of biological disease-modifying anti-rheumatic drugs (DMARDs), RA remains an incurable life-long disease. Advancements in peptide-based vaccination may open new avenues for treating autoimmune diseases, including RA, by inducing immune tolerance while maintaining normal immune function. We have already demonstrated the efficacy of a potent vaccine against RA, consisting of the mouse major histocompatibility complex class II (Aq) protein bound to the immunodominant type II collagen peptide COL2259-273, which needed to be galactosylated at position 264. To translate the vaccine to humans and to further enhance vaccine efficacy, we modified the glycine residue at position 265 and conjugated it with the human DRB1∗04:01 molecule. Remarkably, this modified vaccine (named DR4-AL179) provided robust effectiveness in suppressing arthritis in DRB1∗04:01-expressing mice without the need for galactosylation at position 264. DR4-AL179 vaccination induces tolerance involving multiple immunoregulatory pathways, including the activation of V-type immunoglobulin domain-containing suppressor of T cell activation (VISTA)-positive nonconventional regulatory T cells, which contribute to a potent suppressive response preventing arthritis development in mice. This modified RA vaccine offers a novel therapeutic potential for human autoimmune diseases.

Place, publisher, year, edition, pages
Elsevier, 2025
Keywords
COL2, immune checkpoints, MHCII, regulatory T cells, rheumatoid arthritis, T cell tolerance, tolerogenic, vaccine, VISTA
National Category
Immunology in the Medical Area Rheumatology Autoimmunity and Inflammation
Identifiers
urn:nbn:se:umu:diva-238834 (URN)10.1016/j.ymthe.2025.04.034 (DOI)40285352 (PubMedID)2-s2.0-105004434061 (Scopus ID)
Funder
Swedish Research Council, 2024-02575Novo Nordisk FoundationKnut and Alice Wallenberg Foundation, 2019.0059Lars Hierta Memorial FoundationSwedish Rheumatism AssociationKing Gustaf V Jubilee Fund, SGI-2023-0993
Available from: 2025-06-04 Created: 2025-06-04 Last updated: 2025-06-04
Kumari, R., Lindgren, C., Kumar, R., Forsgren, N., Andersson, C. D., Ekström, F. & Linusson, A. (2024). Enzyme dynamics determine the potency and selectivity of inhibitors targeting disease-transmitting mosquitoes. ACS - Infectious Diseases, 10(10), 3664-3680
Open this publication in new window or tab >>Enzyme dynamics determine the potency and selectivity of inhibitors targeting disease-transmitting mosquitoes
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2024 (English)In: ACS - Infectious Diseases, E-ISSN 2373-8227, Vol. 10, no 10, p. 3664-3680Article in journal (Refereed) Published
Abstract [en]

Vector control of mosquitoes with insecticides is an important tool for preventing the spread of mosquito-borne diseases including malaria, dengue, chikungunya, and Zika. Development of active ingredients for insecticides are urgently needed because existing agents exhibit off-target toxicity and are subject to increasing resistance. We therefore seek to develop noncovalent inhibitors of the validated insecticidal target acetylcholinesterase 1 (AChE1) from mosquitoes. Here we use molecular dynamics simulations to identify structural properties essential for the potency of reversible inhibitors targeting AChE1 from Anopheles gambiae (AgAChE1), the malaria-transmitting mosquito, and for selectivity relative to the vertebrate Mus musculus AChE (mAChE). We show that the collective motions of apo AgAChE1 and mAChE differ, with AgAChE1 exhibiting less dynamic movement. Opening and closing of the gorge, which regulates access to the catalytic triad, is enabled by different mechanisms in the two species, which could be linked to their differing amino acid sequences. Inhibitor binding reduced the overall magnitude of dynamics of AChE. In particular, more potent inhibitors reduced the flexibility of the Ω loop at the entrance of the gorge. The selectivity of inhibitors for AgAChE1 over mAChE derives from the positioning of the α-helix lining the binding gorge. Our findings emphasize the need to consider dynamics when developing inhibitors targeting this enzyme and highlight factors needed to create potent and selective AgAChE1 inhibitors that could serve as active ingredients to combat disease-transmitting mosquitoes.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2024
Keywords
acetylcholinesterase, inhibitors, molecular dynamics, mosquitoes, vector control
National Category
Organic Chemistry Biochemistry Molecular Biology
Identifiers
urn:nbn:se:umu:diva-230609 (URN)10.1021/acsinfecdis.4c00531 (DOI)001315756000001 ()39291389 (PubMedID)2-s2.0-85205394034 (Scopus ID)
Funder
Swedish Research Council, 2018-05176Swedish Research Council, 2022-04331
Available from: 2024-10-08 Created: 2024-10-08 Last updated: 2025-02-20Bibliographically approved
Tükenmez, H., Singh, P., Sarkar, S., Çakır, M., Oliveira, A. H., Lindgren, C., . . . Johansson, J. (2023). A highly substituted ring-fused 2-pyridone compound targeting PrfA and the efflux regulator BrtA in listeria monocytogenes [Letter to the editor]. mBio, 14(3), Article ID e0044923.
Open this publication in new window or tab >>A highly substituted ring-fused 2-pyridone compound targeting PrfA and the efflux regulator BrtA in listeria monocytogenes
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2023 (English)In: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 14, no 3, article id e0044923Article in journal, Letter (Refereed) Published
Abstract [en]

Listeria monocytogenes is a facultative Gram-positive bacterium that causes listeriosis, a severe foodborne disease. We previously discovered that ring-fused 2-pyridone compounds can decrease virulence factor expression in Listeria by binding and inactivating the PrfA virulence activator. In this study, we tested PS900, a highly substituted 2-pyridone that was recently discovered to be bactericidal to other Gram-positive pathogenic bacteria, such as Staphylococcus aureus and Enterococcus faecalis. We show that PS900 can interact with PrfA and reduce the expression of virulence factors. Unlike previous ring-fused 2-pyridones shown to inactivate PrfA, PS900 had an additional antibacterial activity and was found to potentiate sensitivity toward cholic acid. Two PS900-tolerant mutants able to grow in the presence of PS900 carried mutations in the brtA gene, encoding the BrtA repressor. In wild-type (WT) bacteria, cholic acid binds and inactivates BrtA, thereby alleviating the expression of the multidrug transporter MdrT. Interestingly, we found that PS900 also binds to BrtA and that this interaction causes BrtA to dissociate from its binding site in front of the mdrT gene. In addition, we observed that PS900 potentiated the effect of different osmolytes. We suggest that the increased potency of cholic acid and osmolytes to kill bacteria in the presence of PS900 is due to the ability of the latter to inhibit general efflux, through a yet-unknown mechanism. Our data indicate that thiazolino 2-pyridones constitute an attractive scaffold when designing new types of antibacterial agents.

IMPORTANCE: Bacteria resistant to one or several antibiotics are a very large problem, threatening not only treatment of infections but also surgery and cancer treatments. Thus, new types of antibacterial drugs are desperately needed. In this work, we show that a new generation of substituted ring-fused 2-pyridones not only inhibit Listeria monocytogenes virulence gene expression, presumably by inactivating the PrfA virulence regulator, but also potentiate the bactericidal effects of cholic acid and different osmolytes. We identified a multidrug repressor as a second target of 2-pyridones. The repressor–2-pyridone interaction displaces the repressor from DNA, thus increasing the expression of a multidrug transporter. In addition, our data suggest that the new class of ring-fused 2-pyridones are efficient efflux inhibitors, possibly explaining why the simultaneous addition of 2-pyridones together with cholic acid or osmolytes is detrimental for the bacterium. This work proves conclusively that 2-pyridones constitute a promising scaffold to build on for future antibacterial drug design.

Place, publisher, year, edition, pages
American Society for Microbiology, 2023
Keywords
2-pyridones, BrtA, Listeria monocytogenes, PrfA, antibacterial, antibiotic
National Category
Biochemistry Molecular Biology Microbiology in the medical area Organic Chemistry
Research subject
molecular cell biology
Identifiers
urn:nbn:se:umu:diva-214132 (URN)10.1128/mbio.00449-23 (DOI)000975886700001 ()37120759 (PubMedID)2-s2.0-85172894238 (Scopus ID)
Funder
Familjen Erling-Perssons StiftelseNIH (National Institutes of Health), RO1AI134847-01A1NIH (National Institutes of Health), 1IU19AI157797-01Olle Engkvists stiftelseVinnova, 2019-05491Swedish Research Council, 2020-02005Swedish Research Council, 2018-04589Swedish Research Council, 202105040J
Available from: 2023-09-05 Created: 2023-09-05 Last updated: 2025-02-20Bibliographically approved
Vidal-Albalat, A., Kindahl, T., Rajeshwari, R., Lindgren, C., Forsgren, N., Kitur, S., . . . Linusson, A. (2023). Structure-activity relationships reveal beneficial selectivity profiles of inhibitors targeting acetylcholinesterase of disease-transmitting mosquitoes. Journal of Medicinal Chemistry, 66(9), 6333-6353
Open this publication in new window or tab >>Structure-activity relationships reveal beneficial selectivity profiles of inhibitors targeting acetylcholinesterase of disease-transmitting mosquitoes
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2023 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 66, no 9, p. 6333-6353Article in journal (Refereed) Published
Abstract [en]

Insecticide resistance jeopardizes the prevention of infectious diseases such as malaria and dengue fever by vector control of disease-transmitting mosquitoes. Effective new insecticidal compounds with minimal adverse effects on humans and the environment are therefore urgently needed. Here, we explore noncovalent inhibitors of the well-validated insecticidal target acetylcholinesterase (AChE) based on a 4-thiazolidinone scaffold. The 4-thiazolidinones inhibit AChE1 from the mosquitoes Anopheles gambiae and Aedes aegypti at low micromolar concentrations. Their selectivity depends primarily on the substitution pattern of the phenyl ring; halogen substituents have complex effects. The compounds also feature a pendant aliphatic amine that was important for activity; little variation of this group is tolerated. Molecular docking studies suggested that the tight selectivity profiles of these compounds are due to competition between two binding sites. Three 4-thiazolidinones tested for in vivo insecticidal activity had similar effects on disease-transmitting mosquitoes despite a 10-fold difference in their in vitro activity.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2023
National Category
Organic Chemistry Medicinal Chemistry
Identifiers
urn:nbn:se:umu:diva-208264 (URN)10.1021/acs.jmedchem.3c00234 (DOI)000979350900001 ()37094110 (PubMedID)2-s2.0-85156231351 (Scopus ID)
Funder
Swedish Research Council, 2017-00664The Kempe Foundations
Available from: 2023-05-24 Created: 2023-05-24 Last updated: 2024-11-27Bibliographically approved
Stael, S., Sabljić, I., Audenaert, D., Andersson, T., Tsiatsiani, L., Kumpf, R. P., . . . Van Breusegem, F. (2023). Structure-function study of a Ca2+-independent metacaspase involved in lateral root emergence. Proceedings of the National Academy of Sciences of the United States of America, 120(22), Article ID e2303480120.
Open this publication in new window or tab >>Structure-function study of a Ca2+-independent metacaspase involved in lateral root emergence
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2023 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 120, no 22, article id e2303480120Article in journal (Refereed) Published
Abstract [en]

Metacaspases are part of an evolutionarily broad family of multifunctional cysteine proteases, involved in disease and normal development. As the structure-function relationship of metacaspases remains poorly understood, we solved the X-ray crystal structure of an Arabidopsis thaliana type II metacaspase (AtMCA-IIf) belonging to a particular subgroup not requiring calcium ions for activation. To study metacaspase activity in plants, we developed an in vitro chemical screen to identify small molecule metacaspase inhibitors and found several hits with a minimal thioxodihydropyrimidine-dione structure, of which some are specific AtMCA-IIf inhibitors. We provide mechanistic insight into the basis of inhibition by the TDP-containing compounds through molecular docking onto the AtMCA-IIf crystal structure. Finally, a TDP-containing compound (TDP6) effectively hampered lateral root emergence in vivo, probably through inhibition of metacaspases specifically expressed in the endodermal cells overlying developing lateral root primordia. In the future, the small compound inhibitors and crystal structure of AtMCA-IIf can be used to study metacaspases in other species, such as important human pathogens, including those causing neglected diseases.

Place, publisher, year, edition, pages
Proceedings of the National Academy of Sciences (PNAS), 2023
Keywords
AtMCA-IIf crystal structure, cysteine protease, lateral root development, metacaspase, small chemical inhibitor
National Category
Plant Biotechnology
Identifiers
urn:nbn:se:umu:diva-210280 (URN)10.1073/pnas.2303480120 (DOI)001041275500007 ()37216519 (PubMedID)2-s2.0-85159833521 (Scopus ID)
Funder
Knut and Alice Wallenberg Foundation, 2018.0026Knut and Alice Wallenberg Foundation, 2021.0071
Available from: 2023-06-21 Created: 2023-06-21 Last updated: 2025-04-24Bibliographically approved
Lindgren, C., Forsgren, N., Hoster, N., Akfur, C., Artursson, E., Edvinsson, L., . . . Linusson, A. (2022). Broad-Spectrum Antidote Discovery by Untangling the Reactivation Mechanism of Nerve-Agent-Inhibited Acetylcholinesterase. Chemistry - A European Journal, 28(40), Article ID e202200678.
Open this publication in new window or tab >>Broad-Spectrum Antidote Discovery by Untangling the Reactivation Mechanism of Nerve-Agent-Inhibited Acetylcholinesterase
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2022 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 28, no 40, article id e202200678Article in journal (Refereed) Published
Abstract [en]

Reactivators are vital for the treatment of organophosphorus nerve agent (OPNA) intoxication but new alternatives are needed due to their limited clinical applicability. The toxicity of OPNAs stems from covalent inhibition of the essential enzyme acetylcholinesterase (AChE), which reactivators relieve via a chemical reaction with the inactivated enzyme. Here, we present new strategies and tools for developing reactivators. We discover suitable inhibitor scaffolds by using an activity-independent competition assay to study non-covalent interactions with OPNA-AChEs and transform these inhibitors into broad-spectrum reactivators. Moreover, we identify determinants of reactivation efficiency by analysing reactivation and pre-reactivation kinetics together with structural data. Our results show that new OPNA reactivators can be discovered rationally by exploiting detailed knowledge of the reactivation mechanism of OPNA-inhibited AChE.

Place, publisher, year, edition, pages
John Wiley & Sons, 2022
Keywords
drug design, kinetics, nerve agent antidotes, reaction mechanisms, structural biology
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:umu:diva-196525 (URN)10.1002/chem.202200678 (DOI)000807066300001 ()35420233 (PubMedID)2-s2.0-85131325691 (Scopus ID)
Funder
Swedish Research Council, 2018-07152Swedish Research Council Formas, 2019-02496Swedish Research Council, 2018-05176
Available from: 2022-06-14 Created: 2022-06-14 Last updated: 2025-05-19Bibliographically approved
Lindgren, C., Tyagi, M., Viljanen, J., Toms, J., Ge, C., Zhang, N., . . . Linusson, A. (2018). Dynamics Determine Signaling in a Multicomponent System Associated with Rheumatoid Arthritis. Journal of Medicinal Chemistry, 61(11), 4774-4790
Open this publication in new window or tab >>Dynamics Determine Signaling in a Multicomponent System Associated with Rheumatoid Arthritis
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2018 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 61, no 11, p. 4774-4790Article in journal (Refereed) Published
Abstract [en]

Strategies that target multiple components are usually required for treatment of diseases originating from complex biological systems. The multicomponent system consisting of the DR4 major histocompatibility complex type II molecule, the glycopeptide CI1259-273 from type II collagen, and a T-cell receptor is associated with development of rheumatoid arthritis (RA). We introduced non-native amino acids and amide bond isosteres into CI1259-273 and investigated the effect on binding to DR4 and the subsequent T-cell response. Molecular dynamics simulations revealed that complexes between DR4 and derivatives of CI1259-273 were highly dynamic. Signaling in the overall multicomponent system was found to depend on formation of an appropriate number of dynamic intramolecular hydrogen bonds between DR4 and CI1259-273, together with the positioning of the galactose moiety of CI1259-273 in the DR4 binding groove. Interestingly, the system tolerated modifications at several positions in CI1259-273, indicating opportunities to use analogues to increase our understanding of how rheumatoid arthritis develops and for evaluation as vaccines to treat RA.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2018
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:umu:diva-150782 (URN)10.1021/acs.jmedchem.7b01880 (DOI)000435613100008 ()29727183 (PubMedID)2-s2.0-85046659349 (Scopus ID)
Available from: 2018-08-31 Created: 2018-08-31 Last updated: 2023-03-24Bibliographically approved
Knutsson, S., Engdahl, C., Kumari, R., Forsgren, N., Lindgren, C., Kindahl, T., . . . Linusson, A. (2018). Noncovalent Inhibitors of Mosquito Acetylcholinesterase 1 with Resistance-Breaking Potency. Journal of Medicinal Chemistry, 61(23), 10545-10557
Open this publication in new window or tab >>Noncovalent Inhibitors of Mosquito Acetylcholinesterase 1 with Resistance-Breaking Potency
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2018 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 61, no 23, p. 10545-10557Article in journal (Refereed) Published
Abstract [en]

Resistance development in insects significantly threatens the important benefits obtained by insecticide usage in vector control of disease-transmitting insects. Discovery of new chemical entities with insecticidal activity is highly desired in order to develop new insecticide candidates. Here, we present the design, synthesis, and biological evaluation of phenoxyacetamide-based inhibitors of the essential enzyme acetylcholinesterase 1 (AChE1). AChE1 is a validated insecticide target to control mosquito vectors of, e.g., malaria, dengue, and Zika virus infections. The inhibitors combine a mosquito versus human AChE selectivity with a high potency also for the resistance-conferring mutation G122S; two properties that have proven challenging to combine in a single compound. Structure activity relationship analyses and molecular dynamics simulations of inhibitor protein complexes have provided insights that elucidate the molecular basis for these properties. We also show that the inhibitors demonstrate in vivo insecticidal activity on disease-transmitting mosquitoes. Our findings support the concept of noncovalent, selective, and resistance-breaking inhibitors of AChE1 as a promising approach for future insecticide development.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2018
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:umu:diva-154812 (URN)10.1021/acs.jmedchem.8b01060 (DOI)000453488200014 ()30339371 (PubMedID)2-s2.0-85058504373 (Scopus ID)
Funder
Swedish Research Council, 2014-4218Swedish Research Council, 2014-2636
Available from: 2019-01-07 Created: 2019-01-07 Last updated: 2023-03-23Bibliographically approved
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