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Publications (10 of 65) Show all publications
Rullo, M., La Spada, G., Miniero, D. V., Gottinger, A., Catto, M., Delre, P., . . . Pisani, L. (2023). Bioisosteric replacement based on 1,2,4-oxadiazoles in the discovery of 1H-indazole-bearing neuroprotective MAO B inhibitors. European Journal of Medicinal Chemistry, 255, Article ID 115352.
Open this publication in new window or tab >>Bioisosteric replacement based on 1,2,4-oxadiazoles in the discovery of 1H-indazole-bearing neuroprotective MAO B inhibitors
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2023 (English)In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 255, article id 115352Article in journal (Refereed) Published
Abstract [en]

Following a hybridization strategy, a series of 5-substituted-1H-indazoles were designed and evaluated in vitro as inhibitors of human monoamine oxidase (hMAO) A and B. Among structural modifications, the bioisostere-based introduction of 1,2,4-oxadiazole ring returned the most potent and selective human MAO B inhibitor (compound 20, IC50 = 52 nM, SI > 192). The most promising inhibitors were studied in cell-based neuroprotection models of SH-SY5Y and astrocytes line against H2O2. Moreover, preliminary drug-like features (aqueous solubility at pH 7.4; hydrolytic stability at acidic and neutral pH) were assessed for selected 1,2,4-oxadiazoles and compared to amide analogues through RP-HPLC methods. Molecular docking simulations highlighted the crucial role of molecular flexibility in providing a better shape complementarity for compound 20 within MAO B enzymatic cleft than rigid analogue 18. Enzymatic kinetics analysis along with thermal stability curves (Tm shift = +2.9 °C) provided clues of a tight-binding mechanism for hMAO B inhibition by 20.

Place, publisher, year, edition, pages
Elsevier, 2023
Keywords
1, 2, 4-Oxadiazole, 1H-indazole, Bioisostere, Monoamine oxidases, Neuroprotection, Tight-binder
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:umu:diva-208948 (URN)10.1016/j.ejmech.2023.115352 (DOI)001009007300001 ()37178666 (PubMedID)2-s2.0-85158816858 (Scopus ID)
Available from: 2023-06-02 Created: 2023-06-02 Last updated: 2023-09-05Bibliographically 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: 2023-09-05Bibliographically 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)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: 2023-06-21Bibliographically 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: 2023-03-24Bibliographically approved
Rullo, M., Cipolloni, M., Catto, M., Colliva, C., Miniero, D. V., Latronico, T., . . . Pisani, L. (2022). Probing Fluorinated Motifs onto Dual AChE-MAO B Inhibitors: Rational Design, Synthesis, Biological Evaluation, and Early-ADME Studies. Journal of Medicinal Chemistry, 65(5), 3962-3977
Open this publication in new window or tab >>Probing Fluorinated Motifs onto Dual AChE-MAO B Inhibitors: Rational Design, Synthesis, Biological Evaluation, and Early-ADME Studies
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2022 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 65, no 5, p. 3962-3977Article in journal (Refereed) Published
Abstract [en]

Bioisosteric H/F or CH2OH/CF2H replacement was introduced in coumarin derivatives previously characterized as dual AChE-MAO B inhibitors to probe the effects on both inhibitory potency and drug-likeness. Along with in vitro screening, we investigated early-ADME parameters related to solubility and lipophilicity (Sol7.4, CHI7.4, log D7.4), oral bioavailability and central nervous system (CNS) penetration (PAMPA-HDM and PAMPA-blood–brain barrier (BBB) assays, Caco-2 bidirectional transport study), and metabolic liability (half-lives and clearance in microsomes, inhibition of CYP3A4). Both specific and nonspecific tissue toxicities were determined in SH-SY5Y and HepG2 lines, respectively. Compound 15 bearing a −CF2H motif emerged as a water-soluble, orally bioavailable CNS-permeant potent inhibitor of both human AChE (IC50 = 550 nM) and MAO B (IC50 = 8.2 nM, B/A selectivity > 1200). Moreover, 15 behaved as a safe and metabolically stable neuroprotective agent, devoid of cytochrome liability.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2022
National Category
Medicinal Chemistry Pharmacology and Toxicology
Identifiers
urn:nbn:se:umu:diva-193084 (URN)10.1021/acs.jmedchem.1c01784 (DOI)000772205900017 ()35195417 (PubMedID)2-s2.0-85125816423 (Scopus ID)
Available from: 2022-03-18 Created: 2022-03-18 Last updated: 2023-09-05Bibliographically approved
Wiktelius, D., Allgardsson, A., Bergström, T., Hoster, N., Akfur, C., Forsgren, N., . . . Ekstrom, F. (2021). In Situ Assembly of Choline Acetyltransferase Ligands by a Hydrothiolation Reaction Reveals Key Determinants for Inhibitor Design. Angewandte Chemie International Edition, 60(2), 813-819
Open this publication in new window or tab >>In Situ Assembly of Choline Acetyltransferase Ligands by a Hydrothiolation Reaction Reveals Key Determinants for Inhibitor Design
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2021 (English)In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 60, no 2, p. 813-819Article in journal (Refereed) Published
Abstract [en]

The potential drug target choline acetyltransferase (ChAT) catalyses the production of the neurotransmitter acetylcholine in cholinergic neurons, T-cells, and B-cells. Herein, we show that arylvinylpyridiniums (AVPs), the most widely studied class of ChAT inhibitors, act as substrate in an unusual coenzyme A-dependent hydrothiolation reaction. This in situ synthesis yields an adduct that is the actual enzyme inhibitor. The adduct is deeply buried in the active site tunnel of ChAT and interactions with a hydrophobic pocket near the choline binding site have major implications for the molecular recognition of inhibitors. Our findings clarify the inhibition mechanism of AVPs, establish a drug modality that exploits a target-catalysed reaction between exogenous and endogenous precursors, and provide new directions for the development of ChAT inhibitors with improved potency and bioactivity.

Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2021
Keywords
choline acetyltransferase, coenzyme A, drug discovery, hydrothiolation, in situ assembly
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-177255 (URN)10.1002/anie.202011989 (DOI)000590562300001 ()33079431 (PubMedID)2-s2.0-85097185291 (Scopus ID)
Available from: 2020-12-07 Created: 2020-12-07 Last updated: 2023-03-24Bibliographically approved
Minina, E. A., Staal, J., Alvarez, V. E., Berges, J. A., Berman-Frank, I., Beyaert, R., . . . Bozhkov, P. V. (2020). Classification and Nomenclature of Metacaspases and Paracaspases: No More Confusion with Caspases [Letter to the editor]. Molecular Cell, 77(5), 927-929
Open this publication in new window or tab >>Classification and Nomenclature of Metacaspases and Paracaspases: No More Confusion with Caspases
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2020 (English)In: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 77, no 5, p. 927-929Article in journal, Letter (Refereed) Published
Place, publisher, year, edition, pages
Elsevier, 2020
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-169450 (URN)10.1016/j.molcel.2019.12.020 (DOI)000519770000001 ()32142688 (PubMedID)2-s2.0-85080130145 (Scopus ID)
Projects
Bio4Energy
Funder
Bio4Energy
Available from: 2020-04-03 Created: 2020-04-03 Last updated: 2024-07-02Bibliographically approved
Andersson, C. D., Mishra, B. K., Forsgren, N., Ekström, F. & Linusson, A. (2020). Physical Mechanisms Governing Substituent Effects on Arene-Arene Interactions in a Protein Milieu. Journal of Physical Chemistry B, 124(30), 6529-6539
Open this publication in new window or tab >>Physical Mechanisms Governing Substituent Effects on Arene-Arene Interactions in a Protein Milieu
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2020 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 124, no 30, p. 6529-6539Article in journal (Refereed) Published
Abstract [en]

Arene-arene interactions play important roles in protein-ligand complex formation. Here, we investigate the characteristics of arene-arene interactions between small organic molecules and aromatic amino acids in protein interiors. The study is based on X-ray crystallographic data and quantum mechanical calculations using the enzyme acetylcholinesterase and selected inhibitory ligands as a model system. It is shown that the arene substituents of the inhibitors dictate the strength of the interaction and the geometry of the resulting complexes. Importantly, the calculated interaction energies correlate well with the measured inhibitor potency. Non-hydrogen substituents strengthened all interaction types in the protein milieu, in keeping with results for benzene dimer model systems. The interaction energies were dispersion-dominated, but substituents that induced local dipole moments increased the electrostatic contribution and thus yielded more strongly bound complexes. These findings provide fundamental insights into the physical mechanisms governing arene-arene interactions in the protein milieu and thus into molecular recognition between proteins and small molecules.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2020
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-174580 (URN)10.1021/acs.jpcb.0c03778 (DOI)000558655900006 ()32610016 (PubMedID)2-s2.0-85089615974 (Scopus ID)
Funder
Swedish Research Council, 2018-05176
Available from: 2020-08-28 Created: 2020-08-28 Last updated: 2023-03-24Bibliographically approved
Rogne, P., Andersson, D., Grundström, C., Sauer-Eriksson, E., Linusson, A. & Wolf-Watz, M. (2019). Nucleation of an Activating Conformational Change by a Cation−Π Interaction. Biochemistry, 58(32), 3408-3412
Open this publication in new window or tab >>Nucleation of an Activating Conformational Change by a Cation−Π Interaction
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2019 (English)In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 58, no 32, p. 3408-3412Article in journal (Refereed) Published
Abstract [en]

As a key molecule in biology, adenosine triphosphate (ATP) has numerous crucial functions in, for instance, energetics, post-translational modifications, nucleotide biosynthesis, and cofactor metabolism. Here, we have discovered an intricate interplay between the enzyme adenylate kinase and its substrate ATP. The side chain of an arginine residue was found to be an efficient sensor of the aromatic moiety of ATP through the formation of a strong cation−π interaction. In addition to recognition, the interaction was found to have dual functionality. First, it nucleates the activating conformational transition of the ATP binding domain and also affects the specificity in the distant AMP binding domain. In light of the functional consequences resulting from the cation−π interaction, it is possible that the mode of ATP recognition may be a useful tool in enzyme design.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2019
National Category
Organic Chemistry Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-162099 (URN)10.1021/acs.biochem.9b00538 (DOI)000480827100002 ()31339702 (PubMedID)2-s2.0-85070652179 (Scopus ID)
Available from: 2019-08-14 Created: 2019-08-14 Last updated: 2023-03-23Bibliographically 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
Projects
Probing molecular interactions of protein-ligand complexes guided by an integration of chemometrics and molecular modelling [2008-03672_VR]; Umeå UniversityProbing Non-Covalent Interactions in Protein-Ligand Complexes [2011-04840_VR]; Umeå UniversityVector Control by Multiple Classes of Small Organic Compounds to Combat Mosquito-Borne Infectious Diseases and Suppress Insecticide Resistance [2014-02636_VR]; Umeå UniversityVector Control by Multiple Classes of Small Organic Compounds to Combat Mosquito-Borne Infectious Diseases and Suppress Insecticide Resistance [2014-04218_VR]; Umeå UniversityTargeting Fundamental Aspects of Protein-Ligand Interactions to Improve Computer-Aided Molecular Design [2014-04675_VR]; Umeå UniversityNew insecticides for sustainable and effective vector control of disease-transmitting mosquitoes [2017-00664_VR]; Umeå UniversityElucidating the Mechanism of Therapeutic Antidotes for Neurotoxicity caused by Nerve Agents and Pesticides [2018-05176_VR]; Umeå University
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-0063-8912

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