| 1. |
- Benediktsdottir, Andrea, 1990-, et al.
(författare)
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Antibacterial sulfonimidamide-based oligopeptides as type I signal peptidase inhibitors : Synthesis and biological evaluation
- 2021
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Ingår i: European Journal of Medicinal Chemistry. - : Elsevier. - 0223-5234 .- 1768-3254. ; 224
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Tidskriftsartikel (refereegranskat)abstract
- Oligopeptide boronates with a lipophilic tail are known to inhibit the type I signal peptidase in E. coli, which is a promising drug target for developing novel antibiotics. Antibacterial activity depends on these oligopeptides having a cationic modification to increase their permeation. Unfortunately, this modification is associated with cytotoxicity, motivating the need for novel approaches. The sulfonimidamide functionality has recently gained much interest in drug design and discovery, as a means of introducing chirality and an imine-handle, thus allowing for the incorporation of additional substituents. This in turn can tune the chemical and biological properties, which are here explored. We show that introducing the sulfonimidamide between the lipophilic tail and the peptide in a series of signal peptidase inhibitors resulted in antibacterial activity, while the sulfonamide isostere and previously known non-cationic analogs were inactive. Additionally, we show that replacing the sulfonamide with a sulfonimidamide resulted in decreased cytotoxicity, and similar results were seen by adding a cationic sidechain to the sulfonimidamide motif. This is the first report of incorporation of the sulfonimidamide functional group into bioactive peptides, more specifically into antibacterial oligopeptides, and evaluation of its biological effects.
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| 2. |
- Benediktsdóttir, Andrea, 1990-
(författare)
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Design and synthesis of enzyme inhibitors against Gram-negative bacteria : Targeting protein secretion and lipid A biosynthesis
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The discovery and implementation of antibiotics for clinical use was unquestionably the greatest medical breakthrough of the 20th century. However, the widespread misuse and overuse of these antibiotics, has led to the rapid emergence and spread of antibiotic resistance. The 'ESKAPE' pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) represent a critical threat in multidrug-resistant infections. The Gram-negative species (such as E. coli, K. pneumoniae, P. aeruginosa, and A. baumannii) are especially difficult to combat due to their dual-membrane and efficient efflux pumps, which limit the efficacy of many antibiotics. Despite significant efforts, no new antibiotic class with a new mechanism of action has been approved for Gram-negative pathogens in over five decades. New chemical classes of antibacterial compounds targeting distinct mechanisms within Gram-negative bacteria are therefore urgently called for. The studies outlined in this thesis addresses these challenges by designing and synthesising new antibacterial compounds of three distinct chemical classes, which interact with two unrealized targets, LepB and LpxH, in Gram-negative bacteria, including E. coli and K. pneumoniae. This thesis investigates the effect of macrocyclization of type I signal peptidase (LepB) inhibitors by optimizing previously studied linear lipopeptide boronic acids and esters to address their cytotoxic and hemolytic liabilities while retaining activity. This resulted in the synthesis of first-in-class P2-P1' boronic ester-linked macrocycles with modest improvement of cytotoxicity but at the cost of reduced antibacterial activity (paper I). In another optimization attempt, isosteric modification of LepB inhibitors was explored by introducing the sulfonimidamide motif into oligopeptide boronic esters, displaying potent LepB inhibitors. Prior to the synthesis of these pseudopeptides novel methods were developed to introduce sulfonimidamides into peptides on solid-phase (paper II and paper III). These studies demonstrated the potential of sulfonimidamides to alter the drug properties and which was herein compared to a corresponding sulfonamide. Additionally, the thesis describes how a new series of LpxH inhibitors, meta-sulfonamidobenzamide-based sulfonyl piperazine derivatives, were identified and prepared. This resulted in inhibitors with wild-type activity without causing hemolysis, cell toxicity or inhibition of hERG ion channel (paper IV). In summary, strategies suitable for the synthesis and optimization of new antibacterial compounds targeting two distinct Gram-negative bacterial targets, LepB and LpxH, are described in this thesis. While there was no success in separating toxicity from antibacterial activity of the LepB inhibitors, these results highlight the challenge in this task and contribute to a better understanding of the structure-activity and toxicity relationships of such inhibitors and provide strategies that could be of use in antibacterial drug discovery. The identification of the meta-sulfonamidobenzamide derivatives offer promising LpxH-targeting hits with the potential for further development in future hit-to-lead antibacterial programs.
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| 3. |
- Eriksson, Carl, 1981-, et al.
(författare)
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Clinical effectiveness of golimumab in ulcerative colitis : a prospective multicentre study based on the Swedish IBD Quality Register, SWIBREG
- 2021
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 56:11, s. 1304-1311
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Clinical trials demonstrated that golimumab is effective in anti-TNF naïve patients with ulcerative colitis. We aimed to assess the clinical effectiveness of golimumab in a real-world setting. Materials and methods: This was a prospective cohort study, conducted at 16 Swedish hospitals. Data were collected using an electronic case report form. Patients with active ulcerative colitis, defined as Mayo endoscopic subscore ≥2 were eligible for inclusion. The primary outcomes were clinical effectiveness at 12 weeks and 52 weeks, i.e. response (defined as a decrease in Mayo score by ≥3 points or 30% from baseline) and remission (defined as a Mayo score of ≤2 with no individual subscores >1). Results: Fifty patients were included. At study entry, 70% were previously exposed to anti-TNF, 16% to vedolizumab, and 96% to immunomodulators. The 12 and 52-week drug continuation rates were 37/50 (74%) and 23/50 (46%), respectively. The 12-week response rate was 14/50 (28%), the remission rate, 8/50 (16%) and the corresponding figures at week 52 were 13/50 (26%) and 10/50 (20%). Among patients who continued golimumab, the median Mayo score decreased from 7 (6–9) at baseline to 1 (0–5) at 52 weeks (p <.01) and the faecal calprotectin decreased from 862 (335–1759) µg/g to 90 (34–169) µg/g (p <.01). Clinical response at week 12 was highly predictive of clinical remission at week 52 (adjusted OR: 73.1; 95% CI: 4.5‒1188.9). Conclusions: The majority of golimumab treated patients represented a treatment refractory patient-group. Despite this, our results confirm that golimumab is an effective therapy in ulcerative colitis.
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| 4. |
- Grinkevich, Vera V., et al.
(författare)
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Novel Allosteric Mechanism of Dual p53/MDM2 and p53/MDM4 Inhibition by a Small Molecule
- 2022
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Ingår i: Frontiers in Molecular Biosciences. - : Frontiers Media S.A.. - 2296-889X. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Restoration of the p53 tumor suppressor for personalised cancer therapy is a promising treatment strategy. However, several high-affinity MDM2 inhibitors have shown substantial side effects in clinical trials. Thus, elucidation of the molecular mechanisms of action of p53 reactivating molecules with alternative functional principle is of the utmost importance. Here, we report a discovery of a novel allosteric mechanism of p53 reactivation through targeting the p53 N-terminus which promotes inhibition of both p53/MDM2 (murine double minute 2) and p53/MDM4 interactions. Using biochemical assays and molecular docking, we identified the binding site of two p53 reactivating molecules, RITA (reactivation of p53 and induction of tumor cell apoptosis) and protoporphyrin IX (PpIX). Ion mobility-mass spectrometry revealed that the binding of RITA to serine 33 and serine 37 is responsible for inducing the allosteric shift in p53, which shields the MDM2 binding residues of p53 and prevents its interactions with MDM2 and MDM4. Our results point to an alternative mechanism of blocking p53 interaction with MDM2 and MDM4 and may pave the way for the development of novel allosteric inhibitors of p53/MDM2 and p53/MDM4 interactions.
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| 5. |
- Lu, Lu, 1984-, et al.
(författare)
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Synthesis and in vitro biological evaluation of quinolinyl pyrimidines targeting type II NADH-dehydrogenase (NDH-2)
- 2022
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Ingår i: ACS - Infectious Diseases. - : American Chemical Society (ACS). - 2373-8227. ; 8:3, s. 482-498
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Tidskriftsartikel (refereegranskat)abstract
- Type II NADH dehydrogenase (NDH-2) is an essential component of electron transfer in many microbial pathogens but has remained largely unexplored as a potential drug target. Previously, quinolinyl pyrimidines were shown to inhibit Mycobacterium tuberculosis NDH-2, as well as the growth of the bacteria [Shirude, P. S.; ACS Med. Chem. Lett. 2012, 3, 736−740]. Here, we synthesized a number of novel quinolinyl pyrimidines and investigated their properties. In terms of inhibition of the NDH-2 enzymes from M. tuberculosis and Mycobacterium smegmatis, the best compounds were of similar potency to previously reported inhibitors of the same class (half-maximal inhibitory concentration (IC50) values in the low-μM range). However, a number of the compounds had much better activity against Gram-negative pathogens, with minimum inhibitory concentrations (MICs) as low as 2 μg/mL. Multivariate analyses (partial least-squares (PLS) and principle component analysis (PCA)) showed that overall ligand charge was one of the most important factors in determining antibacterial activity, with patterns that varied depending on the particular bacterial species. In some cases (e.g., mycobacteria), there was a clear correlation between the IC50 values and the observed MICs, while in other instances, no such correlation was evident. When tested against a panel of protozoan parasites, the compounds failed to show activity that was not linked to cytotoxicity. Further, a strong correlation between hydrophobicity (estimated as clog P) and cytotoxicity was revealed; more hydrophobic analogues were more cytotoxic. By contrast, antibacterial MIC values and cytotoxicity were not well correlated, suggesting that the quinolinyl pyrimidines can be optimized further as antimicrobial agents.
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| 6. |
- Miethke, Marcus, et al.
(författare)
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Towards the sustainable discovery and development of new antibiotics
- 2021
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Ingår i: Nature Reviews Chemistry. - : Springer Nature. - 2397-3358. ; 5:10, s. 726-749
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Forskningsöversikt (refereegranskat)abstract
- An ever-increasing demand for novel antimicrobials to treat life-threatening infections caused by the global spread of multidrug-resistant bacterial pathogens stands in stark contrast to the current level of investment in their development, particularly in the fields of natural-product-derived and synthetic small molecules. New agents displaying innovative chemistry and modes of action are desperately needed worldwide to tackle the public health menace posed by antimicrobial resistance. Here, our consortium presents a strategic blueprint to substantially improve our ability to discover and develop new antibiotics. We propose both short-term and long-term solutions to overcome the most urgent limitations in the various sectors of research and funding, aiming to bridge the gap between academic, industrial and political stakeholders, and to unite interdisciplinary expertise in order to efficiently fuel the translational pipeline for the benefit of future generations.
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| 7. |
- Nerelius, Fredrik, 1985-, et al.
(författare)
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Patient-reported Outcome after Surgical Evacuation of Postoperative Spinal Epidural Hematomas at One-year Follow-up
- 2024
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Ingår i: Spine. - : Wolters Kluwer. - 0362-2436 .- 1528-1159. ; 49:10, s. 701-707
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Tidskriftsartikel (refereegranskat)abstract
- STUDY DESIGN: Retrospective analysis of prospectively collected data from the National Swedish Spine Register (Swespine).OBJECTIVE: To evaluate the effects of symptomatic spinal epidural hematoma (SSEH) requiring reoperation on one-year patient-reported outcome measures (PROMs) in a large cohort of patients treated surgically for lumbar spinal stenosis (LSS).SUMMARY OF BACKGROUND DATA: Studies exploring the outcomes of reoperations after SSEH are scarce and often lack validated outcome measures. As SSEH is considered a serious complication, understanding of the outcome following hematoma evacuation is important.MATERIALS AND METHODS: After retrieving data from 2007 to 2017 from Swespine, we included all patients with LSS without concomitant spondylolisthesis who were treated surgically with decompression without fusion. Patients with evacuated SSEH were identified in the registry. Back/leg pain numerical rating scales (NRS), the Oswestry Disability Index (ODI), and EQ VAS were used for outcome assessment. PROMs before and one-year after decompression surgery were compared between evacuated patients and all other patients. Multivariate linear regression was performed to determine if hematoma evacuation predicted inferior one-year PROM scores.RESULTS: A total of 113 patients with an evacuated SSEH were compared with 19527 patients with no evacuation. One-year after decompression surgery, both groups showed significant improvement in all PROMs. When comparing the two groups' one-year improvement there were no significant differences in any PROM. The proportion of patients achieving the minimum important change was not significantly different for any PROM. Multivariate linear regression found that hematoma evacuation significantly predicted inferior one-year ODI (β=4.35, P=0.043), but it was not a significant predictor of inferior NRS Back (β=0.50, P=0.105), NRS Leg (β=0.41, P=0.221), or EQ VAS (β=-1.97, P=0.470). CONCLUSIONS: A surgically evacuated SSEH does not affect outcome in terms of back/leg pain or health-related quality of life. Commonly used PROM surveys may not capture neurologic deficits associated with SSEH.
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| 8. |
- Olanders, Gustav, 1991-
(författare)
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Computational Modeling of Macrocycles and Structure-Based Design of Novel Antibacterial Compounds
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 9. |
- Olanders, Gustav, et al.
(författare)
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Computational studies of molecular pre-organization through macrocyclization : Conformational distribution analysis of closely related non-macrocyclic and macrocyclic analogs
- 2021
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier. - 0968-0896 .- 1464-3391. ; 49
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 10. |
- Olanders, Gustav, et al.
(författare)
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Conformational Analysis of Macrocycles : Comparing General and Specialized Methods
- 2020
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Ingår i: Journal of Computer-Aided Molecular Design. - : Springer Science and Business Media LLC. - 0920-654X .- 1573-4951. ; 34, s. 231-252
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Tidskriftsartikel (refereegranskat)abstract
- 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
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