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  • 1.
    Alogheli, Hiba
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Olanders, Gustav
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Schaal, Wesley
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Brandt, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Anders, Karlén
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Docking of Macrocycles: Comparing Rigid and Flexible Docking in Glide2017Inngår i: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 57, nr 2, s. 190-202Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In recent years, there has been an increased interest in using macrocyclic compounds for drug discovery and development. For docking of these commonly large and flexible compounds to be addressed, a screening and a validation set were assembled from the PDB consisting of 16 and 31 macrocycle-containing protein complexes, respectively. The macrocycles were docked in Glide by rigid docking of pregenerated conformational ensembles produced by the macrocycle conformational sampling method (MCS) in Schrödinger Release 2015-3 or by direct Glide flexible docking after performing ring-templating. The two protocols were compared to rigid docking of pregenerated conformational ensembles produced by an exhaustive Monte Carlo multiple minimum (MCMM) conformational search and a shorter MCMM conformational search (MCMM-short). The docking accuracy was evaluated and expressed as the RMSD between the heavy atoms of the ligand as found in the X-ray structure after refinement and the poses obtained by the docking protocols. The median RMSD values for top-scored poses of the screening set were 0.83, 0.80, 0.88, and 0.58 Å for MCMM, MCMM-short, MCS, and Glide flexible docking, respectively. There was no statistically significant difference in the performance between rigid docking of pregenerated conformations produced by the MCS and direct docking using Glide flexible docking. However, the flexible docking protocol was 2-times faster in docking the screening set compared to that of the MCS protocol. In a final study, the new Prime-MCS method was evaluated in Schrödinger Release 2016-3. This method is faster compared that of to MCS; however, the conformations generated were found to be suboptimal for rigid docking. Therefore, on the basis of timing, accuracy, and ease of set up, standard Glide flexible docking with prior ring-templating is recommended over current gold standard protocols using rigid docking of pregenerated conformational ensembles.

  • 2.
    Lundmark, Fanny
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Preparativ läkemedelskemi.
    Olanders, Gustav
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Rinne, Sara Sophie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Abouzayed, Ayman
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Rosenström, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Preparativ läkemedelskemi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Design, Synthesis, and Evaluation of Linker-Optimised PSMA-Targeting Radioligands2022Inngår i: Pharmaceutics, ISSN 1999-4923, E-ISSN 1999-4923, Vol. 14, nr 5, artikkel-id 1098Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Prostate-specific membrane antigen (PSMA) is overexpressed in the majority of prostate cancer cells and is considered to be an important target for the molecular imaging and therapy of prostate cancer. Herein, we present the design, synthesis, and evaluation of 11 PSMA-binding radioligands with modified linker structures, focusing on the relationship between molecular structure and targeting properties. The linker design was based on 2-naphthyl-L-alanine-tranexamic acid, the linker structure of PSMA-617. X-ray crystal-structure analysis of PSMA and structure-based design were used to generate the linker modifications, suggesting that substitution of tranexamic acid could lead to interactions with Phe546, Trp541, and Arg43 within the binding cavity. After synthesis through SPPS, analogues were labelled with indium-111 and evaluated in vitro for their specific binding, affinity, and cellular retention. Selected compounds were further evaluated in vivo in PSMA-expressing tumour-bearing mice. Based on the results, 2-naphthyl-L-alanine appears to be crucial for good targeting properties, whereas tranexamic acid could be replaced by other substituents. [111In]In-BQ7859, consisting of a 2-naphthyl-L-alanine-L-tyrosine linker, demonstrated favourable targeting properties. The substitution of tranexamic acid for L-tyrosine in the linker led to an improved tumour-to-blood ratio, highlighting [111In]In-BQ7859 as a promising PSMA-targeting radioligand.

    Fulltekst (pdf)
    FULLTEXT01
  • 3.
    Olanders, Gustav
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Computational Modeling of Macrocycles and Structure-Based Design of Novel Antibacterial Compounds2021Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The integration of computational methods into the drug discovery process provides valuable tools to help advance new and improved drugs into the clinic. As medicinal chemists explore novel targets and new areas of chemical space, our computational toolkit must also evolve.

    Macrocycles are high-value scaffolds in medicinal chemistry due to their attractive physiochemical properties and intricate interactions with biomolecules. However, given the significant challenges associated with their synthesis, improved computational tools are required to both understand macrocycle conformation and binding preferences and to also efficiently guide medicinal chemistry efforts. Therefore, this thesis focuses on the evaluation, optimization and application of computational methods for macrocycle drug discovery.

    Our initial work, Paper I, investigated both rigid and flexible macrocycle docking techniques. This showed that rigid docking of conformational ensembles generated using a range of sampling methods could result in significant differences in docking accuracy. Furthermore, we showed that either rigid docking of MD/LLMOD generated conformers or flexible docking could be applied.

    In Paper II, we conducted further investigations of macrocycle conformational sampling by comparing more general sampling methods to those specialized towards macrocyclic scaffolds. The study showed that the general conformational sampling methods perform well compared with the more specialized methods. Our work also shows that the general methods can themselves be modified for improved macrocycle sampling.

    Building on these findings, Paper III compares the conformational preferences of linear ligands and their closely related macrocyclic analogs. Interestingly, our analysis showed that for many of the macrocyclic ensembles they were not significantly more focused towards the bioactive conformation than their linear analogs.

    In Paper IV, our computational toolkit was used to design novel antibacterial macrocycles targeting signal peptidase I. Here we developed macrocyclic compounds with nanomolar inhibitory activity against signal peptidase I, which also showed antibacterial activity.

    Delarbeid
    1. Docking of Macrocycles: Comparing Rigid and Flexible Docking in Glide
    Åpne denne publikasjonen i ny fane eller vindu >>Docking of Macrocycles: Comparing Rigid and Flexible Docking in Glide
    Vise andre…
    2017 (engelsk)Inngår i: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 57, nr 2, s. 190-202Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    In recent years, there has been an increased interest in using macrocyclic compounds for drug discovery and development. For docking of these commonly large and flexible compounds to be addressed, a screening and a validation set were assembled from the PDB consisting of 16 and 31 macrocycle-containing protein complexes, respectively. The macrocycles were docked in Glide by rigid docking of pregenerated conformational ensembles produced by the macrocycle conformational sampling method (MCS) in Schrödinger Release 2015-3 or by direct Glide flexible docking after performing ring-templating. The two protocols were compared to rigid docking of pregenerated conformational ensembles produced by an exhaustive Monte Carlo multiple minimum (MCMM) conformational search and a shorter MCMM conformational search (MCMM-short). The docking accuracy was evaluated and expressed as the RMSD between the heavy atoms of the ligand as found in the X-ray structure after refinement and the poses obtained by the docking protocols. The median RMSD values for top-scored poses of the screening set were 0.83, 0.80, 0.88, and 0.58 Å for MCMM, MCMM-short, MCS, and Glide flexible docking, respectively. There was no statistically significant difference in the performance between rigid docking of pregenerated conformations produced by the MCS and direct docking using Glide flexible docking. However, the flexible docking protocol was 2-times faster in docking the screening set compared to that of the MCS protocol. In a final study, the new Prime-MCS method was evaluated in Schrödinger Release 2016-3. This method is faster compared that of to MCS; however, the conformations generated were found to be suboptimal for rigid docking. Therefore, on the basis of timing, accuracy, and ease of set up, standard Glide flexible docking with prior ring-templating is recommended over current gold standard protocols using rigid docking of pregenerated conformational ensembles.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-318050 (URN)10.1021/acs.jcim.6b00443 (DOI)000395226100010 ()28079375 (PubMedID)
    Forskningsfinansiär
    Swedish Research Council, 521-2014-6711
    Tilgjengelig fra: 2017-03-23 Laget: 2017-03-23 Sist oppdatert: 2021-06-16bibliografisk kontrollert
    2. Conformational Analysis of Macrocycles: Comparing General and Specialized Methods
    Åpne denne publikasjonen i ny fane eller vindu >>Conformational Analysis of Macrocycles: Comparing General and Specialized Methods
    2020 (engelsk)Inngår i: Journal of Computer-Aided Molecular Design, ISSN 0920-654X, E-ISSN 1573-4951, Vol. 34, s. 231-252Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Macrocycles represent an important class of medicinally relevant small molecules due to their interesting biological properties. Therefore, a firm understanding of their conformational preferences is important for drug design. Given the importance of macrocycle-protein modelling in drug discovery, we envisaged that a systematic study of both classical and recent specialized methods would provide guidance for other practitioners within the field. In this study we compare the performance of the general, well established conformational analysis methods Monte Carlo Multiple Minimum (MCMM) and Mixed Torsional/Low-Mode sampling (MTLMOD) with two more recent and specialized macrocycle sampling techniques: MacroModel macrocycle Baseline Search (MD/LLMOD) and Prime macrocycle conformational sampling (PRIME-MCS). Using macrocycles extracted from 44 macrocycle-protein X-ray crystallography complexes, we evaluated each method based on their ability to (i) generate unique conformers, (ii) generate unique macrocycle ring conformations, (iii) identify the global energy minimum, (iv) identify conformers similar to the X-ray ligand conformation after Protein Preparation Wizard treatment (X-ray(ppw)), and (v) to the X-ray(ppw) ring conformation. Computational speed was also considered. In addition, conformational coverage, as defined by the number of conformations identified, was studied. In order to study the relative energies of the bioactive conformations, the energy differences between the global energy minima and the energy minimized X-ray(ppw) structures and, the global energy minima and the MCMM-Exhaustive (1,000,000 search steps) generated conformers closest to the X-ray(ppw) structure, were calculated and analysed. All searches were performed using relatively short run times (10,000 steps for MCMM, MTLMOD and MD/LLMOD). To assess the performance of the methods, they were compared to an exhaustive MCMM search using 1,000,000 search steps for each of the 44 macrocycles (requiring ca 200 times more CPU time). Prior to our analysis, we also investigated if the general search methods MCMM and MTLMOD could also be optimized for macrocycle conformational sampling. Taken together, our work concludes that the more general methods can be optimized for macrocycle modelling by slightly adjusting the settings around the ring closure bond. In most cases, MCMM and MTLMOD with either standard or enhanced settings performed well in comparison to the more specialized macrocycle sampling methods MD/LLMOD and PRIME-MCS. When using enhanced settings for MCMM and MTLMOD, the X-ray(ppw) conformation was regenerated with the greatest accuracy. The, MD/LLMOD emerged as the most efficient method for generating the global energy minima. Graphic abstract

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-340864 (URN)10.1007/s10822-020-00277-2 (DOI)000515183900002 ()31965404 (PubMedID)
    Forskningsfinansiär
    Swedish Research Council, 521-2014-6711
    Tilgjengelig fra: 2018-02-04 Laget: 2018-02-04 Sist oppdatert: 2021-06-16bibliografisk kontrollert
    3. Computational studies of molecular pre-organization through macrocyclization: Conformational distribution analysis of closely related non-macrocyclic and macrocyclic analogs
    Åpne denne publikasjonen i ny fane eller vindu >>Computational studies of molecular pre-organization through macrocyclization: Conformational distribution analysis of closely related non-macrocyclic and macrocyclic analogs
    2021 (engelsk)Inngår i: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 49, artikkel-id 116399Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Macrocycles form an important compound class in medicinal chemistry due to their interesting structural and biological properties. To help design macrocycles, it is important to understand how the conformational preferences are affected upon macrocyclization of a lead compound. To address this, we collected a unique data set of protein-ligand complexes containing "non-macrocyclic" ("linear") ligands matched with macrocyclic analogs binding to the same protein in a similar pose. Out of the 39 co-crystallized ligands considered, 10 were linear and 29 were macrocyclic. To enable a more general analysis, 128 additional ligands from the publications associated with these protein data bank entries were added to the data set. Using in total 167 collected ligands, we investigated if the conformers in the macrocyclic conformational ensembles were more similar to the bioactive conformation in comparison to the conformers of their linear counterparts. Unexpectedly, in most cases the macrocycle conformational ensemble distributions were not very different from those of the linear compounds. Thus, care should be taken when designing macrocycles with the aim to focus their conformational preference towards the bioactive conformation. We also set out to investigate potential conformational flexibility differences between the two compound classes, computational energy window settings and evaluate a literature metric for approximating the conformational focusing on the bioactive conformation.

    sted, utgiver, år, opplag, sider
    ElsevierElsevier, 2021
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-446542 (URN)10.1016/j.bmc.2021.116399 (DOI)000707122300005 ()34601455 (PubMedID)
    Forskningsfinansiär
    Swedish Research Council, 521-2014-6711
    Tilgjengelig fra: 2021-06-21 Laget: 2021-06-21 Sist oppdatert: 2024-01-15bibliografisk kontrollert
    4. Boronic ester-linked macrocyclic lipopeptides as serine protease inhibitors targeting Escherichia coli type I signal peptidase
    Åpne denne publikasjonen i ny fane eller vindu >>Boronic ester-linked macrocyclic lipopeptides as serine protease inhibitors targeting Escherichia coli type I signal peptidase
    Vise andre…
    2018 (engelsk)Inngår i: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 157, s. 1346-1360Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Type I signal peptidase, with its vital role in bacterial viability, is a promising but underexploited antibacterial drug target. In the light of steadily increasing rates of antimicrobial resistance, we have developed novel macrocyclic lipopeptides, linking P2 and P1' by a boronic ester warhead, capable of inhibiting Escherichia coli type I signal peptidase (EcLepB) and exhibiting good antibacterial activity. Structural modifications of the macrocyclic ring, the peptide sequence and the lipophilic tail led us to 14 novel macrocyclic boronic esters. It could be shown that macrocyclization is well tolerated in terms of EcLepB inhibition and antibacterial activity. Among the synthesized macrocycles, potent enzyme inhibitors in the low nanomolar range (e.g. compound 42f, EcLepB IC50 = 29 nM) were identified also showing good antimicrobial activity (e.g. compound 42b, E. coli WT MIC = 16 μg/mL). The unique macrocyclic boronic esters described here were based on previously published linear lipopeptidic EcLepB inhibitors in an attempt to address cytotoxicity and hemolysis. We show herein that structural changes to the macrocyclic ring influence both the cytotoxicity and hemolytic activity suggesting that the P2 to P1' linker provide means for optimizing off-target effects. However, for the present set of compounds we were not able to separate the antibacterial activity and cytotoxic effect.

    Emneord
    Antibacterial lipopeptides, Bacterial type I signal peptidase, Escherichia coli type I signal peptidase (EcLepB), P2–P1′ boronic ester-linked macrocycles
    HSV kategori
    Forskningsprogram
    Infektionssjukdomar
    Identifikatorer
    urn:nbn:se:uu:diva-362335 (URN)10.1016/j.ejmech.2018.08.086 (DOI)000447480000096 ()30196059 (PubMedID)
    Forskningsfinansiär
    Swedish Research Council, 2014-6711Swedish Research Council, 2015-05406Swedish Research Council, 2017-03953
    Merknad

    N.S. and L.L. share first authorship.

    Tilgjengelig fra: 2018-10-03 Laget: 2018-10-03 Sist oppdatert: 2021-06-16bibliografisk kontrollert
    Fulltekst (pdf)
    UUThesis_G-Olanders-2021
    Download (jpg)
    presentationsbild
  • 4.
    Olanders, Gustav
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Läkemedelsdesign och läkemedelsutveckling.
    Alogheli, Hiba
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Läkemedelsdesign och läkemedelsutveckling.
    Brandt, Peter
    Med Chem, Res,Early Dev Cardiovascular,Renal,Metab, BioPharmaceuticals R&D,AstraZeneca, Gothenburg, Sweden.
    Karlén, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Läkemedelsdesign och läkemedelsutveckling.
    Conformational Analysis of Macrocycles: Comparing General and Specialized Methods2020Inngår i: Journal of Computer-Aided Molecular Design, ISSN 0920-654X, E-ISSN 1573-4951, Vol. 34, s. 231-252Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Macrocycles represent an important class of medicinally relevant small molecules due to their interesting biological properties. Therefore, a firm understanding of their conformational preferences is important for drug design. Given the importance of macrocycle-protein modelling in drug discovery, we envisaged that a systematic study of both classical and recent specialized methods would provide guidance for other practitioners within the field. In this study we compare the performance of the general, well established conformational analysis methods Monte Carlo Multiple Minimum (MCMM) and Mixed Torsional/Low-Mode sampling (MTLMOD) with two more recent and specialized macrocycle sampling techniques: MacroModel macrocycle Baseline Search (MD/LLMOD) and Prime macrocycle conformational sampling (PRIME-MCS). Using macrocycles extracted from 44 macrocycle-protein X-ray crystallography complexes, we evaluated each method based on their ability to (i) generate unique conformers, (ii) generate unique macrocycle ring conformations, (iii) identify the global energy minimum, (iv) identify conformers similar to the X-ray ligand conformation after Protein Preparation Wizard treatment (X-ray(ppw)), and (v) to the X-ray(ppw) ring conformation. Computational speed was also considered. In addition, conformational coverage, as defined by the number of conformations identified, was studied. In order to study the relative energies of the bioactive conformations, the energy differences between the global energy minima and the energy minimized X-ray(ppw) structures and, the global energy minima and the MCMM-Exhaustive (1,000,000 search steps) generated conformers closest to the X-ray(ppw) structure, were calculated and analysed. All searches were performed using relatively short run times (10,000 steps for MCMM, MTLMOD and MD/LLMOD). To assess the performance of the methods, they were compared to an exhaustive MCMM search using 1,000,000 search steps for each of the 44 macrocycles (requiring ca 200 times more CPU time). Prior to our analysis, we also investigated if the general search methods MCMM and MTLMOD could also be optimized for macrocycle conformational sampling. Taken together, our work concludes that the more general methods can be optimized for macrocycle modelling by slightly adjusting the settings around the ring closure bond. In most cases, MCMM and MTLMOD with either standard or enhanced settings performed well in comparison to the more specialized macrocycle sampling methods MD/LLMOD and PRIME-MCS. When using enhanced settings for MCMM and MTLMOD, the X-ray(ppw) conformation was regenerated with the greatest accuracy. The, MD/LLMOD emerged as the most efficient method for generating the global energy minima. Graphic abstract

    Fulltekst (pdf)
    fulltext
  • 5.
    Olanders, Gustav
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Läkemedelsdesign och läkemedelsutveckling.
    Brandt, Peter
    AstraZeneca, Gothenburg, Sweden.
    Sköld, Christian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Läkemedelsdesign och läkemedelsutveckling.
    Karlen, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Läkemedelsdesign och läkemedelsutveckling.
    Computational studies of molecular pre-organization through macrocyclization: Conformational distribution analysis of closely related non-macrocyclic and macrocyclic analogs2021Inngår i: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 49, artikkel-id 116399Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Macrocycles form an important compound class in medicinal chemistry due to their interesting structural and biological properties. To help design macrocycles, it is important to understand how the conformational preferences are affected upon macrocyclization of a lead compound. To address this, we collected a unique data set of protein-ligand complexes containing "non-macrocyclic" ("linear") ligands matched with macrocyclic analogs binding to the same protein in a similar pose. Out of the 39 co-crystallized ligands considered, 10 were linear and 29 were macrocyclic. To enable a more general analysis, 128 additional ligands from the publications associated with these protein data bank entries were added to the data set. Using in total 167 collected ligands, we investigated if the conformers in the macrocyclic conformational ensembles were more similar to the bioactive conformation in comparison to the conformers of their linear counterparts. Unexpectedly, in most cases the macrocycle conformational ensemble distributions were not very different from those of the linear compounds. Thus, care should be taken when designing macrocycles with the aim to focus their conformational preference towards the bioactive conformation. We also set out to investigate potential conformational flexibility differences between the two compound classes, computational energy window settings and evaluate a literature metric for approximating the conformational focusing on the bioactive conformation.

    Fulltekst (pdf)
    fulltext
  • 6.
    Szałaj, Natalia
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Lu, Lu
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Strukturbiologi.
    Benediktsdottir, Andrea
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Zamaratski, Edouard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Cao, Sha
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Olanders, Gustav
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Hedgecock, Charles
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Karlen, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Erdélyi, Máté
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Hughes, Diarmaid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Mowbray, Sherry L
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Brandt, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Boronic ester-linked macrocyclic lipopeptides as serine protease inhibitors targeting Escherichia coli type I signal peptidase2018Inngår i: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 157, s. 1346-1360Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Type I signal peptidase, with its vital role in bacterial viability, is a promising but underexploited antibacterial drug target. In the light of steadily increasing rates of antimicrobial resistance, we have developed novel macrocyclic lipopeptides, linking P2 and P1' by a boronic ester warhead, capable of inhibiting Escherichia coli type I signal peptidase (EcLepB) and exhibiting good antibacterial activity. Structural modifications of the macrocyclic ring, the peptide sequence and the lipophilic tail led us to 14 novel macrocyclic boronic esters. It could be shown that macrocyclization is well tolerated in terms of EcLepB inhibition and antibacterial activity. Among the synthesized macrocycles, potent enzyme inhibitors in the low nanomolar range (e.g. compound 42f, EcLepB IC50 = 29 nM) were identified also showing good antimicrobial activity (e.g. compound 42b, E. coli WT MIC = 16 μg/mL). The unique macrocyclic boronic esters described here were based on previously published linear lipopeptidic EcLepB inhibitors in an attempt to address cytotoxicity and hemolysis. We show herein that structural changes to the macrocyclic ring influence both the cytotoxicity and hemolytic activity suggesting that the P2 to P1' linker provide means for optimizing off-target effects. However, for the present set of compounds we were not able to separate the antibacterial activity and cytotoxic effect.

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