24 results on '"Clara T. Schoeder"'
Search Results
2. Design, synthesis, and structure-activity relationships of diindolylmethane derivatives as cannabinoid CB
- Author
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Andhika B, Mahardhika, Anastasiia, Ressemann, Sarah E, Kremers, Mariana S, Gregório Castanheira, Clara T, Schoeder, Christa E, Müller, and Thanigaimalai, Pillaiyar
- Abstract
3,3'-Diindolylmethane (DIM), a natural product-derived compound formed upon ingestion of cruciferous vegetables, was recently described to act as a partial agonist of the anti-inflammatory cannabinoid (CB) receptor subtype CB
- Published
- 2022
3. <scp>RosettaCM</scp> for antibodies with very long <scp>HCDR3s</scp> and low template availability
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James E. Crowe, Jens Meiler, Clara T. Schoeder, Samuel Schmitz, and Pranav Kodali
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Modeling software ,Protein Conformation ,Computer science ,Process (engineering) ,Antigen-Antibody Complex ,Computational biology ,Molecular Dynamics Simulation ,Biochemistry ,Antibodies ,Article ,Structural Biology ,Humans ,Homology modeling ,Antigens ,Databases, Protein ,Molecular Biology ,Protocol (science) ,biology ,Molecular Docking Simulation ,Benchmarking ,Template ,Structural Homology, Protein ,Docking (molecular) ,Benchmark (computing) ,biology.protein ,Antibody ,Algorithms ,Software - Abstract
Antibody-antigen co-crystal structures are a valuable resource for the fundamental understanding of antibody-mediated immunity. Determination of structures with antibodies in complex with their antigens, however, is a laborious task without guarantee of success. Therefore, homology modeling of antibodies and docking to their respective-antigens has become a very important technique to drive antibody and vaccine design. The quality of the antibody modeling process is critical for the success of these endeavors. Here, we compare different computational protocols for predicting antibody structure from sequence in the biomolecular modeling software Rosetta - all of which use multiple existing antibody structures to guide modeling. Specifically, we compare protocols developed solely to predict antibody structure (RosettaAntibody, AbPredict) with a universal homology modeling protocol (RosettaCM). Following recent advances in homology modeling with multiple templates simultaneously, we propose that the use of multiple templates over the same antibody regions may improve modeling performance. To evaluate whether multi-template comparative modeling with RosettaCM can improve the modeling accuracy of antibodies over existing methods, this study compares the performance of the three modeling algorithms when modeling human antibodies taken from antibody-antigen co-crystal structures. In these benchmarking experiments, RosettaCM outperformed other methods when modeling antibodies with long HCDR3s and few available templates.
- Published
- 2021
4. Hydroxamic Acids Immobilized on Resins (HAIRs): Synthesis of Dual‐Targeting HDAC Inhibitors and HDAC Degraders (PROTACs)
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Finn K. Hansen, Alexandra Hamacher, Jens Meiler, Jan J. Bandolik, Martin Roatsch, Clara T. Schoeder, Andrea Schöler, Laura Sinatra, Sanil Bhatia, Matthias U. Kassack, Melf Sönnichsen, and Arndt Borkhardt
- Subjects
MULTITARGET DRUGS ,solid-phase synthesis ,Dual targeting ,DNA damage ,Antineoplastic Agents ,Apoptosis ,Caspase 3 ,Hydroxamic Acids ,010402 general chemistry ,01 natural sciences ,Histone Deacetylases ,Catalysis ,PROTAC ,Chimera (genetics) ,Solid-phase synthesis ,Cell Line, Tumor ,Humans ,POLYPHARMACOLOGY ,Multi‐Target Drugs | Hot Paper ,Molecular Structure ,biology ,010405 organic chemistry ,Chemistry ,Communication ,TEMOZOLOMIDE ,General Chemistry ,Anticancer drug ,Communications ,multi-target drugs ,0104 chemical sciences ,Cell biology ,Histone Deacetylase Inhibitors ,Resins, Synthetic ,Histone ,histone deacetylase ,biology.protein ,Histone deacetylase - Abstract
Inhibition of more than one cancer‐related pathway by multi‐target agents is an emerging approach in modern anticancer drug discovery. Here, based on the well‐established synergy between histone deacetylase inhibitors (HDACi) and alkylating agents, we present the discovery of a series of alkylating HDACi using a pharmacophore‐linking strategy. For the parallel synthesis of the target compounds, we developed an efficient solid‐phase‐supported protocol using hydroxamic acids immobilized on resins (HAIRs) as stable and versatile building blocks for the preparation of functionalized HDACi. The most promising compound, 3 n, was significantly more active in apoptosis induction, activation of caspase 3/7, and formation of DNA damage (γ‐H2AX) than the sum of the activities of either active principle alone. Furthermore, to demonstrate the utility of our preloaded resins, the HAIR approach was successfully extended to the synthesis of a proof‐of‐concept proteolysis‐targeting chimera (PROTAC), which efficiently degrades histone deacetylases., Hydroxamic acids immobilized on resins (HAIRs) were developed and utilized for the library synthesis of DNA‐alkylating HDAC inhibitors and a proof‐of‐concept HDAC degrader (PROTAC). A hybrid compound based on the pharmacophores of chlorambucil and panobinostat was identified as the most promising chimeric HDAC inhibitor and demonstrated improved anticancer properties compared to the sum of the activities of either pharmacophore alone.
- Published
- 2020
5. Hydroxamic Acids Immobilized on Resins (HAIRs): Synthese von Dual‐Target‐HDAC‐Inhibitoren und HDAC‐PROTACs
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Finn K. Hansen, Jens Meiler, Martin Roatsch, Andrea Schöler, Laura Sinatra, Melf Sönnichsen, Arndt Borkhardt, Alexandra Hamacher, Clara T. Schoeder, Jan J. Bandolik, Sanil Bhatia, and Matthias U. Kassack
- Subjects
Dual target ,Solid-phase synthesis ,Biochemistry ,DNA damage ,Chemistry ,General Medicine ,Histone deacetylase - Published
- 2020
6. Structural Comparative Modeling of Multi-Domain F508del CFTR
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Eli Fritz McDonald, Hope Woods, Shannon T. Smith, Minsoo Kim, Clara T. Schoeder, Lars Plate, and Jens Meiler
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congenital, hereditary, and neonatal diseases and abnormalities ,Cystic Fibrosis ,Cystic Fibrosis Transmembrane Conductance Regulator ,respiratory system ,Biochemistry ,digestive system diseases ,respiratory tract diseases ,Models, Structural ,cystic fibrosis, comparative modeling, computational protein modeling, protein folding disease, pharmacological chaperones, VX-809, structure-based drug discovery ,Protein Domains ,Mutation ,Humans ,ddc:610 ,cystic fibrosis ,comparative modeling ,computational protein modeling ,protein folding disease ,pharmacological chaperones ,VX-809 ,structure-based drug discovery ,Molecular Biology - Abstract
Cystic fibrosis (CF) is a rare genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), an epithelial anion channel expressed in several vital organs. Absence of functional CFTR results in imbalanced osmotic equilibrium and subsequent mucus build up in the lungs-which increases the risk of infection and eventually causes death. CFTR is an ATP-binding cassette (ABC) transporter family protein composed of two transmembrane domains (TMDs), two nucleotide binding domains (NBDs), and an unstructured regulatory domain. The most prevalent patient mutation is the deletion of F508 (F508del), making F508del CFTR the primary target for current FDA approved CF therapies. However, no experimental multi-domain F508del CFTR structure has been determined and few studies have modeled F508del using multi-domain WT CFTR structures. Here, we used cryo-EM density data and Rosetta comparative modeling (RosettaCM) to compare a F508del model with published experimental data on CFTR NBD1 thermodynamics. We then apply this modeling method to generate multi-domain WT and F508del CFTR structural models. These models demonstrate the destabilizing effects of F508del on NBD1 and the NBD1/TMD interface in both the inactive and active conformation of CFTR. Furthermore, we modeled F508del/R1070W and F508del bound to the CFTR corrector VX-809. Our models reveal the stabilizing effects of VX-809 on multi-domain models of F508del CFTR and pave the way for rational design of additional drugs that target F508del CFTR for treatment of CF.
- Published
- 2022
7. Structural comparative modeling of multi-domain ΔF508 CFTR
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Minsoo Kim, Lars Plate, Eli Fritz McDonald, Shannon T. Smith, Jens Meiler, Hope Woods, and Clara T. Schoeder
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congenital, hereditary, and neonatal diseases and abnormalities ,Mutation ,biology ,Chemistry ,Mutant ,ATP-binding cassette transporter ,Transporter ,medicine.disease ,medicine.disease_cause ,Cystic fibrosis ,Cystic fibrosis transmembrane conductance regulator ,Cell biology ,Transmembrane domain ,Mutant protein ,medicine ,biology.protein - Abstract
Cystic Fibrosis (CF) is a common genetic disease caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), an epithelial anion channel expressed in several vital organs. Absence of functional CFTR results in imbalanced osmotic equilibrium and subsequent mucus build up in the lungs - which increases the risk of infection and eventually causes death. CFTR is an ATP binding cassette (ABC) transporter composed of two transmembrane domains (TMDs), two nucleotide binding domains (NBDs), and an unstructured regulatory domain. The most prevalent patient mutation is the deletion of F508 (ΔF508), making ΔF508 CFTR the primary target for current FDA approved CF therapies. However, no experimental multi-domain ΔF508 CFTR structure has been determined and few studies have modeled ΔF508 using multi-domain WT CFTR structures. Here, we used cryo-EM density data and Rosetta comparative modeling (RosettaCM) to compare a ΔF508 model with published experimental data on CFTR NBD1 thermodynamics. We then apply this modeling method to generate multi-domain WT and ΔF508 CFTR structural models. These models demonstrate the destabilizing effects of ΔF508 on NBD1 and the NBD1/TMD interface in both the closed and open conformation of CFTR. Furthermore, we modeled ΔF508/R1070W and ΔF508 bound to the CFTR corrector VX-809. Our models reveal the stabilizing effects of R1070W and VX-809 on multi-domain models of ΔF508 CFTR and pave the way for rational design of additional drugs that target ΔF508 CFTR for treatment of CF.Author SummaryProtein’s three-dimension shape determines their function, so when genetic mutation compromises the shape of vital proteins, it may cause disease. Such is the case in Cystic Fibrosis, a chronic genetic disease caused by mutations in the protein Cystic Fibrosis Transmembrane Conductance Regulator. Here, we work backwards from the shape of the wild-type protein – found in healthy people, to computationally model the shape of the most common Cystic Fibrosis mutant. Our computer models reveal distinct defects in the shape of the mutant Cystic Fibrosis Transmembrane Conductance Regulator protein in the area surrounding the mutation. We also model an important FDA approved Cystic Fibrosis drug, VX-809, into the mutant protein structure and show how VX-809 stabilizes the protein around the location of the mutation. The method we developed will pave the way for computational drug design for Cystic Fibrosis.
- Published
- 2021
8. Design, synthesis, and structure–activity relationships of diindolylmethane derivatives as cannabinoid CB 2 receptor agonists
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Andhika B. Mahardhika, Anastasiia Ressemann, Sarah E. Kremers, Mariana S. Gregório Castanheira, Clara T. Schoeder, Christa E. Müller, and Thanigaimalai Pillaiyar
- Subjects
Drug Discovery ,Pharmaceutical Science - Published
- 2022
9. Ligand-Induced and -Independent Internalization of the Chemerin Receptor GPR1
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Jens Meiler, Clara T. Schoeder, Anne S. Czerniak, Annette G. Beck-Sickinger, Philipp Wolf, Tobias F Fischer, Oliver Seitz, and Tina Weiß
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biology ,Chemistry ,media_common.quotation_subject ,biology.protein ,Chemerin ,Ligand (biochemistry) ,Internalization ,GPR1 ,media_common ,Cell biology - Abstract
1. Tight regulation of cytokines is essential for the initiation and resolution of inflammation. Chemerin, a mediator of innate immunity, mainly acts on chemokine-like receptor 1 (CMKLR1) to induce the migration of macrophages and dendritic cells. The role of the second chemerin receptor, G protein-coupled receptor 1 (GPR1), is still unclear. Here we demonstrate that GPR1 shows ligand-induced arrestin3 recruitment and internalization. The chemerin C-terminus triggers this activation by folding into a loop structure, binding to aromatic residues in the extracellular loops of GPR1. While this overall binding mode is shared between GPR1 and CMKLR1, differences in their respective extracellular loop 2 allowed for the design of the first GPR1-selective peptide. However, our results suggest that ligand-induced arrestin recruitment is not the only mode of action of GPR1. This receptor also displays constitutive internalization and recycling, which allows GPR1 to internalize inactive peptides efficiently by an activation-independent pathway. Our results demonstrate that GPR1 takes a dual role in regulating chemerin activity: As a signaling receptor for arrestin-based signaling on one hand, and as a scavenging receptor with broader ligand specificity on the other.
- Published
- 2021
10. Development of Chromen-4-one Derivatives as (Ant)agonists for the Lipid-Activated G Protein-Coupled Receptor GPR55 with Tunable Efficacy
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Mario Funke, Anne Meyer, Andhika B Mahardhika, Clara T. Schoeder, Dominik Thimm, Thomas Blaschke, and Christa E. Müller
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chemistry.chemical_classification ,Chemistry ,Stereochemistry ,General Chemical Engineering ,Neurodegeneration ,General Chemistry ,medicine.disease ,lcsh:Chemistry ,Complementation ,Enzyme ,lcsh:QD1-999 ,GPR55 ,medicine ,Potency ,Receptor ,EC50 ,G protein-coupled receptor - Abstract
The lipid-activated G protein-coupled receptor (GPCR) GPR55 has been proposed as a drug target for the treatment of chronic diseases including inflammation, neurodegeneration, neuropathic pain, metabolic diseases, and cancer. A series of chromen-4-one-2-carboxylic acid derivatives was synthesized with the aim to obtain potent and selective ligands for GPR55 by (i) attachment of a variety of substituted 8-benzamido residues, (ii) substitution in position 6 by halogen atoms, and (iii) thioation of the 4-oxo function. The compounds were investigated in β-arrestin recruitment assays using enzyme complementation. Depending on the substitution pattern, a spectrum of efficacies was obtained ranging from (partial) agonists to antagonists. 6-Chloro-8-(3-((5-cyclohexylpentyl)oxy)benzamido)-4-oxo-4H-chromene-2-carboxylic acid (74, PSB-18251) displayed the highest efficacy of the series combined with high potency (EC50 0.196 μM). 6-Chloro-8-(3-(heptyloxy)benzamido)-4-oxo-4H-chromene-2-carboxylic acid (76, PSB-18337) ...
- Published
- 2019
11. Epitope-focused immunogen design based on the ebolavirus glycoprotein HR2-MPER region
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Clara T. Schoeder, Pavlo Gilchuk, Amandeep K. Sangha, Kaitlyn V. Ledwitch, Delphine C. Malherbe, Xuan Zhang, Elad Binshtein, Lauren E. Williamson, Cristina E. Martina, Jinhui Dong, Erica Armstrong, Rachel Sutton, Rachel Nargi, Jessica Rodriguez, Natalia Kuzmina, Brooke Fiala, Neil P. King, Alexander Bukreyev, James E. Crowe, and Jens Meiler
- Subjects
Immunology ,Hemorrhagic Fever, Ebola ,Antibodies, Viral ,Ebolavirus ,Antibodies, Neutralizing ,Microbiology ,Epitopes ,Virology ,Genetics ,Animals ,Parasitology ,Rabbits ,Molecular Biology ,Glycoproteins - Abstract
The three human pathogenic ebolaviruses: Zaire (EBOV), Bundibugyo (BDBV), and Sudan (SUDV) virus, cause severe disease with high fatality rates. Epitopes of ebolavirus glycoprotein (GP) recognized by antibodies with binding breadth for all three ebolaviruses are of major interest for rational vaccine design. In particular, the heptad repeat 2 –membrane-proximal external region (HR2-MPER) epitope is relatively conserved between EBOV, BDBV, and SUDV GP and targeted by human broadly-neutralizing antibodies. To study whether this epitope can serve as an immunogen for the elicitation of broadly-reactive antibody responses, protein design in Rosetta was employed to transplant the HR2-MPER epitope identified from a co-crystal structure with the known broadly-reactive monoclonal antibody (mAb) BDBV223 onto smaller scaffold proteins. From computational analysis, selected immunogen designs were produced as recombinant proteins and functionally validated, leading to the identification of a sterile alpha motif (SAM) domain displaying the BDBV-HR2-MPER epitope near its C terminus as a promising candidate. The immunogen was fused to one component of a self-assembling, two-component nanoparticle and tested for immunogenicity in rabbits. Robust titers of cross-reactive serum antibodies to BDBV and EBOV GPs and moderate titers to SUDV GP were induced following immunization. To confirm the structural composition of the immunogens, solution NMR studies were conducted and revealed structural flexibility in the C-terminal residues of the epitope. Overall, our study represents the first report on an epitope-focused immunogen design based on the structurally challenging BDBV-HR2-MPER epitope.
- Published
- 2022
12. Ligand-binding and -scavenging of the chemerin receptor GPR1
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Tina Weiß, Jens Meiler, Clara T. Schoeder, Annette G. Beck-Sickinger, Oliver Seitz, Anne S. Czerniak, Tobias F Fischer, and Philipp Wolf
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0301 basic medicine ,Arrestins ,media_common.quotation_subject ,570 Biologie ,CMKLR1 ,Ligands ,GPR1 ,Receptors, G-Protein-Coupled ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,GPCR ,ddc:570 ,Adipokine ,Arrestin ,Fluorescence Resonance Energy Transfer ,Chemerin ,Humans ,Atypical chemokine receptor ,Receptor ,Internalization ,Molecular Biology ,G protein-coupled receptor ,media_common ,Pharmacology ,Inflammation ,Binding Sites ,Microscopy, Confocal ,biology ,Chemistry ,Cell Biology ,Ligand (biochemistry) ,Immunity, Innate ,Cell biology ,Protein Structure, Tertiary ,Molecular Docking Simulation ,030104 developmental biology ,HEK293 Cells ,Mutagenesis ,030220 oncology & carcinogenesis ,biology.protein ,Molecular Medicine ,Receptors, Chemokine ,Original Article ,Chemokines ,Peptides ,Protein Binding - Abstract
Tight regulation of cytokines is essential for the initiation and resolution of inflammation. Chemerin, a mediator of innate immunity, mainly acts on chemokine-like receptor 1 (CMKLR1) to induce the migration of macrophages and dendritic cells. The role of the second chemerin receptor, G protein-coupled receptor 1 (GPR1), is still unclear. Here we demonstrate that GPR1 shows ligand-induced arrestin3 recruitment and internalization. The chemerin C-terminus triggers this activation by folding into a loop structure, binding to aromatic residues in the extracellular loops of GPR1. While this overall binding mode is shared between GPR1 and CMKLR1, differences in their respective extracellular loop 2 allowed for the design of the first GPR1-selective peptide. However, our results suggest that ligand-induced arrestin recruitment is not the only mode of action of GPR1. This receptor also displays constitutive internalization, which allows GPR1 to internalize inactive peptides efficiently by an activation-independent pathway. Our results demonstrate that GPR1 takes a dual role in regulating chemerin activity: as a signaling receptor for arrestin-based signaling on one hand, and as a scavenging receptor with broader ligand specificity on the other. Graphic abstract Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659 Universität Leipzig (1039)
- Published
- 2021
13. Cyclic Analogues of the Chemerin C-Terminus Mimic a Loop Conformation Essential for Activating the Chemokine-like Receptor 1
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Jens Meiler, Annette G. Beck-Sickinger, Tristan Zellmann, Tobias F Fischer, Clara T. Schoeder, and Jan Stichel
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Protein Conformation ,CMKLR1 ,01 natural sciences ,Peptides, Cyclic ,03 medical and health sciences ,Mice ,Drug Discovery ,Chemerin ,Animals ,Humans ,Binding site ,Receptor ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,Binding Sites ,biology ,C-terminus ,Mutagenesis ,Ligand (biochemistry) ,Cyclic peptide ,0104 chemical sciences ,Molecular Docking Simulation ,010404 medicinal & biomolecular chemistry ,chemistry ,biology.protein ,Biophysics ,Molecular Medicine ,Cattle ,Receptors, Chemokine ,Chemokines - Abstract
The chemokine-like receptor 1 (CMKLR1) is a promising target for treating autoinflammatory diseases, cancer, and reproductive disorders. However, the interaction between CMKLR1 and its protein-ligand chemerin remains uncharacterized, and no drugs targeting this interaction have passed clinical trials. Here, we identify the binding mode of chemerin-9, the C-terminus of chemerin, at the receptor by combining complementary mutagenesis with structure-based modeling. Incorporating our experimental data, we present a detailed model of this binding site, including experimentally confirmed pairwise interactions for the most critical ligand residues: Chemerin-9 residue F8 binds to a hydrophobic pocket in CMKLR1 formed by the extracellular loop (ECL) 2, while F6 interacts with Y2.68, suggesting a turn-like structure. On the basis of this model, we created the first cyclic peptide with nanomolar activity, confirming the overall binding conformation. This constrained agonist mimics the loop conformation adopted by the natural ligand and can serve as a lead compound for future drug design.
- Published
- 2021
14. Predicting susceptibility to SARS-CoV-2 infection based on structural differences in ACE2 across species
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Meena S. Madhur, Jens Meiler, John A. Capra, John P. Wikswo, Clara T. Schoeder, Jacquelyn A. Brown, Matthew R Alexander, Chris Moth, Wenbiao Chen, and Charles D Smart
- Subjects
0301 basic medicine ,Models, Molecular ,Camelus ,Glycosylation ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,viruses ,Wildlife ,Biology ,medicine.disease_cause ,Biochemistry ,Virus ,03 medical and health sciences ,0302 clinical medicine ,Species Specificity ,COVID‐19 ,Pandemic ,angiotensin‐converting enzyme 2 ,medicine ,Genetics ,Animals ,Humans ,Genetic Predisposition to Disease ,Amino Acid Sequence ,Horses ,Molecular Biology ,Phylogeny ,Research Articles ,Coronavirus ,business.industry ,SARS-CoV-2 ,COVID-19 ,Protein Structure, Tertiary ,030104 developmental biology ,protein structural elements ,Receptors, Virus ,Livestock ,Identification (biology) ,Angiotensin-Converting Enzyme 2 ,business ,Sequence Alignment ,030217 neurology & neurosurgery ,Biotechnology ,Protein Binding ,Research Article ,severe acute respiratory syndrome coronavirus 2 - Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is the cause of the global pandemic of coronavirus disease‐2019 (COVID‐19). SARS‐CoV‐2 is a zoonotic disease, but little is known about variations in species susceptibility that could identify potential reservoir species, animal models, and the risk to pets, wildlife, and livestock. Certain species, such as domestic cats and tigers, are susceptible to SARS‐CoV‐2 infection, while other species such as mice and chickens are not. Most animal species, including those in close contact with humans, have unknown susceptibility. Hence, methods to predict the infection risk of animal species are urgently needed. SARS‐CoV‐2 spike protein binding to angiotensin‐converting enzyme 2 (ACE2) is critical for viral cell entry and infection. Here we integrate species differences in susceptibility with multiple in‐depth structural analyses to identify key ACE2 amino acid positions including 30, 83, 90, 322, and 354 that distinguish susceptible from resistant species. Using differences in these residues across species, we developed a susceptibility score that predicts an elevated risk of SARS‐CoV‐2 infection for multiple species including horses and camels. We also demonstrate that SARS‐CoV‐2 is nearly optimal for binding ACE2 of humans compared to other animals, which may underlie the highly contagious transmissibility of this virus among humans. Taken together, our findings define potential ACE2 and SARS‐CoV‐2 residues for therapeutic targeting and identification of animal species on which to focus research and protection measures for environmental and public health.
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- 2020
15. Which animals are at risk? Predicting species susceptibility to Covid-19
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Meena S. Madhur, Jens Meiler, John A. Capra, Matthew R Alexander, Jacquelyn A. Brown, John P. Wikswo, W. Chen, Clara T. Schoeder, Christopher W. Moth, and Charles D Smart
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Genetics ,medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,business.industry ,viruses ,Public health ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Wildlife ,Biology ,medicine.disease_cause ,Article ,Pandemic ,medicine ,Identification (biology) ,Livestock ,business ,Coronavirus - Abstract
In only a few months, the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic, leaving physicians, scientists, and public health officials racing to understand, treat, and contain this zoonotic disease. SARS-CoV-2 has made the leap from animals to humans, but little is known about variations in species susceptibility that could identify potential reservoir species, animal models, and the risk to pets, wildlife, and livestock. While there is evidence that certain species, such as cats, are susceptible, the vast majority of animal species, including those in close contact with humans, have unknown susceptibility. Hence, methods to predict their infection risk are urgently needed. SARS-CoV-2 spike protein binding to angiotensin converting enzyme 2 (ACE2) is critical for viral cell entry and infection. Here we identified key ACE2 residues that distinguish susceptible from resistant species using in-depth sequence and structural analyses of ACE2 and its binding to SARS-CoV-2. Our findings have important implications for identification of ACE2 and SARS-CoV-2 residues for therapeutic targeting and identification of animal species with increased susceptibility for infection on which to focus research and protection measures for environmental and public health.
- Published
- 2020
16. Structure-activity relationships of imidazothiazinones and analogs as antagonists of the cannabinoid-activated orphan G protein-coupled receptor GPR18
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Maria Kaleta, Katarzyna Kieć-Kononowicz, Clara T. Schoeder, Agnieszka Olejarz-Maciej, Andhika B Mahardhika, Dorota Łażewska, and Christa E. Müller
- Subjects
0301 basic medicine ,Cannabinoid receptor ,Stereochemistry ,medicine.medical_treatment ,Thiazines ,CHO Cells ,Receptors, G-Protein-Coupled ,Structure-Activity Relationship ,03 medical and health sciences ,Cricetulus ,Drug Discovery ,medicine ,Animals ,Humans ,Structure–activity relationship ,Receptor ,G protein-coupled receptor ,Cannabinoid Receptor Agonists ,Pharmacology ,Orphan receptor ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Organic Chemistry ,Imidazoles ,General Medicine ,030104 developmental biology ,GPR18 ,Cannabinoid - Abstract
GPR18 is a cannabinoid-activated orphan G protein-coupled receptor (GPCR) that is selectively expressed on immune cells. Despite its significant potential as a drug target for inflammatory diseases and cancer immunotherapy, only very few GPR18 ligands have been described to date. In the present study we investigated the structure-activity relationships (SARs) of (Z)-2-(3-(4-chlorobenzyloxy)benzylidene)-6,7-dihydro-2H-imidazo[2,1-b][1,3]thiazin-3(5H)-one (PSB-CB5, 5), the most potent GPR18 antagonist described to date. Analogs were synthesized that exhibit broad modifications of the heterocyclic core and/or variation of substituents at the benzylidene moiety. The compounds were investigated in β-arrestin recruitment assays as inhibitors of human GPR18 activation by tetrahydrocannabinol (THC). Selectivity was assessed versus the cannabinoid receptors (CB1 and CB2) and versus GPR55, another orphan GPCR that interacts with cannabinoids. Phenyloxyalkyloxy-substituted benzylidenethiazinones with long alkyl chains (optimal length: hexamethylene) efficiently blocked GPR18 with similarly high potency as lead structure 5. (Z)-2-(3-(6-(4-Chlorophenoxy)hexyloxy)benzylidene)-6,7-dihydro-2H-imidazo[2,1-b][1,3]thiazin-3(5H)-one (PSB-CB-27, 23) exhibited the best profile: it displayed an IC50 value of 650 nM at GPR18 and showed improved selectivity versus CB receptors as compared to lead structure 5. Importantly, in contrast to 5, which showed only partial inhibition (60%), 23 led to a complete blockade of THC-induced GPR18 activation and is thus a superior tool for target validation. In addition, several compounds, e.g. 18 and 22, were identified as dual GPR18/GPR55 antagonists with similar potency at both targets, and selectivity versus CB receptors.
- Published
- 2018
17. Human V H 1-69 Gene-Encoded Human Monoclonal Antibodies against Staphylococcus aureus IsdB Use at Least Three Distinct Modes of Binding To Inhibit Bacterial Growth and Pathogenesis
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Jens Meiler, Jinhui Dong, Kevin L. Schey, Rachel S. Nargi, Helen M. Parrington, Clara T. Schoeder, Eric P. Skaar, James E. Crowe, Cinque Soto, Monique R. Bennett, Marcus Nagel, and Robin G. Bombardi
- Subjects
Staphylococcus aureus ,medicine.drug_class ,Somatic hypermutation ,Biology ,medicine.disease_cause ,Monoclonal antibody ,Microbiology ,03 medical and health sciences ,Antibiotic resistance ,Antigen ,Virology ,antibody repertoire ,medicine ,computer modeling ,X-ray crystallography ,antibody functions ,030304 developmental biology ,0303 health sciences ,030302 biochemistry & molecular biology ,adaptive immunity ,Acquired immune system ,QR1-502 ,3. Good health ,Humoral immunity ,biology.protein ,Antibody - Abstract
Staphylococcus aureus is an important human pathogen that infects nearly every human tissue. Like most organisms, the acquisition of nutrient iron is necessary for its survival. One route by which it obtains this metal is through the iron-regulated surface determinant (Isd) system that scavenges iron from the hemoglobin of the host. We show that the heavy chain variable region IGHV1-69 gene commonly encodes human monoclonal antibodies (mAbs) targeting IsdB-NEAT2. Remarkably, these antibodies bind to multiple antigenic sites. One class of IGHV1-69-encoded mAbs blocks S. aureus heme acquisition by binding to the heme-binding site of NEAT2, while two additional classes reduce the bacterial burden in vivo by an alternative Fc receptor-mediated mechanism. We further identified clonal lineages of IGHV1-69-encoded mAbs using donor samples, showing that each lineage diversifies during infection by somatic hypermutation. These studies reveal that IGHV1-69-encoded antibodies contribute to a protective immune response, furthering our understanding of the correlates of protection against S. aureus infection. IMPORTANCE The human pathogen Staphylococcus aureus causes a wide range of infections, including skin abscesses and sepsis. There is currently no licensed vaccine to prevent S. aureus infection, and its treatment has become increasingly difficult due to antibiotic resistance. One potential way to inhibit S. aureus pathogenesis is to prevent iron acquisition. The iron-regulated surface determinant (Isd) system has evolved in S. aureus to acquire hemoglobin from the human host as a source of heme-iron. In this study, we investigated the molecular and structural basis for antibody-mediated correlates against a member of the Isd system, IsdB. The association of immunoglobulin heavy chain variable region IGHV1-69 gene-encoded human monoclonal antibodies with the response against S. aureus IsdB is described using structural and functional studies to define the importance of this antibody class. We also determine that somatic hypermutation in the development of these antibodies hinders rather than fine-tunes the immune response to IsdB.
- Published
- 2019
18. Human
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Monique R, Bennett, Jinhui, Dong, Robin G, Bombardi, Cinque, Soto, Helen M, Parrington, Rachel S, Nargi, Clara T, Schoeder, Marcus B, Nagel, Kevin L, Schey, Jens, Meiler, Eric P, Skaar, and James E, Crowe
- Subjects
Proteomics ,Staphylococcus aureus ,Antibodies, Monoclonal ,adaptive immunity ,Therapeutics and Prevention ,Crystallography, X-Ray ,Immunity, Humoral ,humoral immunity ,antibody repertoire ,Humans ,monoclonal antibodies ,computer modeling ,Research Article ,X-ray crystallography ,antibody functions - Abstract
The human pathogen Staphylococcus aureus causes a wide range of infections, including skin abscesses and sepsis. There is currently no licensed vaccine to prevent S. aureus infection, and its treatment has become increasingly difficult due to antibiotic resistance. One potential way to inhibit S. aureus pathogenesis is to prevent iron acquisition. The iron-regulated surface determinant (Isd) system has evolved in S. aureus to acquire hemoglobin from the human host as a source of heme-iron. In this study, we investigated the molecular and structural basis for antibody-mediated correlates against a member of the Isd system, IsdB. The association of immunoglobulin heavy chain variable region IGHV1-69 gene-encoded human monoclonal antibodies with the response against S. aureus IsdB is described using structural and functional studies to define the importance of this antibody class. We also determine that somatic hypermutation in the development of these antibodies hinders rather than fine-tunes the immune response to IsdB., Staphylococcus aureus is an important human pathogen that infects nearly every human tissue. Like most organisms, the acquisition of nutrient iron is necessary for its survival. One route by which it obtains this metal is through the iron-regulated surface determinant (Isd) system that scavenges iron from the hemoglobin of the host. We show that the heavy chain variable region IGHV1-69 gene commonly encodes human monoclonal antibodies (mAbs) targeting IsdB-NEAT2. Remarkably, these antibodies bind to multiple antigenic sites. One class of IGHV1-69-encoded mAbs blocks S. aureus heme acquisition by binding to the heme-binding site of NEAT2, while two additional classes reduce the bacterial burden in vivo by an alternative Fc receptor-mediated mechanism. We further identified clonal lineages of IGHV1-69-encoded mAbs using donor samples, showing that each lineage diversifies during infection by somatic hypermutation. These studies reveal that IGHV1-69-encoded antibodies contribute to a protective immune response, furthering our understanding of the correlates of protection against S. aureus infection.
- Published
- 2019
19. Fintiamin: A diketopiperazine from the marine sponge‐derived fungus Eurotium sp
- Author
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Christa E. Müller, Clara T. Schoeder, and Mahmoud Fahmi Elsebai
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Magnetic Resonance Spectroscopy ,Cannabinoid receptor ,Stereochemistry ,medicine.medical_treatment ,Pharmaceutical Science ,CHO Cells ,Diketopiperazines ,Mass spectrometry ,Mass Spectrometry ,Cricetulus ,Receptor, Cannabinoid, CB1 ,Eurotium ,Drug Discovery ,medicine ,Animals ,Humans ,Binding site ,biology ,Chemistry ,Alkaloid ,Nuclear magnetic resonance spectroscopy ,biology.organism_classification ,Molecular Docking Simulation ,Sponge ,Docking (molecular) ,Cannabinoid - Abstract
The fungus Eurotium sp., derived from the marine sponge Ircinia variabilis, was found to produce a diketopiperazine-indole alkaloid that we named fintiamin (1). Structural elucidation of 1 was achieved by extensive spectroscopic analysis including nuclear magnetic resonance spectroscopy and mass spectrometry. Compound 1 is a lipophilic terpenoid-dipeptide hybrid molecule that shows affinity for the cannabinoid CB1 receptor at low micromolar concentrations. Docking studies based on previous X-ray structures provide a plausible binding pose for compound 1 in the orthosteric binding site of the CB1 receptor.
- Published
- 2021
20. Therapeutic alphavirus cross-reactive E1 human antibodies inhibit viral egress
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Jens Meiler, Robert H. Carnahan, Nurgun Kose, Erica Armstrong, Joseph X. Reidy, Kevin L. Schey, Rachel E. Sutton, James E. Crowe, Kristen M. Reeder, Minh H. Tran, Lauren E. Williamson, Rachel S. Nargi, Benjamin J. Doranz, Edgar Davidson, Arthur S. Kim, William B. Klimstra, W. Hayes McDonald, Andrew Trivette, Mallorie E. Fouch, Michael S. Diamond, Vicky Roy, Kevin W. Bailey, Emma S. Winkler, Galit Alter, Christopher Gainza, Justin G. Julander, Jessica Rodriguez, and Clara T. Schoeder
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Encephalomyelitis, Equine ,Male ,Eastern equine encephalitis virus ,medicine.drug_class ,viruses ,Alphavirus ,Receptors, Fc ,Cross Reactions ,Antibodies, Viral ,medicine.disease_cause ,Monoclonal antibody ,Models, Biological ,Article ,General Biochemistry, Genetics and Molecular Biology ,Epitope ,Cell Line ,Viral Proteins ,Immunity ,medicine ,Animals ,Humans ,Horses ,Antigens, Viral ,Virus Release ,chemistry.chemical_classification ,biology ,Temperature ,Virion ,Antibodies, Monoclonal ,Hydrogen-Ion Concentration ,Virus Internalization ,biology.organism_classification ,Antibodies, Neutralizing ,Virology ,Mice, Inbred C57BL ,Epitope mapping ,chemistry ,biology.protein ,Encephalitis Virus, Eastern Equine ,RNA, Viral ,Female ,Joints ,Antibody ,Glycoprotein ,Chikungunya virus ,Epitope Mapping ,Protein Binding - Abstract
Summary Alphaviruses cause severe arthritogenic or encephalitic disease. The E1 structural glycoprotein is highly conserved in these viruses and mediates viral fusion with host cells. However, the role of antibody responses to the E1 protein in immunity is poorly understood. We isolated E1-specific human monoclonal antibodies (mAbs) with diverse patterns of recognition for alphaviruses (ranging from Eastern equine encephalitis virus [EEEV]-specific to alphavirus cross-reactive) from survivors of natural EEEV infection. Antibody binding patterns and epitope mapping experiments identified differences in E1 reactivity based on exposure of epitopes on the glycoprotein through pH-dependent mechanisms or presentation on the cell surface prior to virus egress. Therapeutic efficacy in vivo of these mAbs corresponded with potency of virus egress inhibition in vitro and did not require Fc-mediated effector functions for treatment against subcutaneous EEEV challenge. These studies reveal the molecular basis for broad and protective antibody responses to alphavirus E1 proteins.
- Published
- 2021
21. Molecular and functional interaction between GPR18 and cannabinoid CB
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Irene, Reyes-Resina, Gemma, Navarro, David, Aguinaga, Enric I, Canela, Clara T, Schoeder, Michał, Załuski, Katarzyna, Kieć-Kononowicz, Carlos A, Saura, Christa E, Müller, and Rafael, Franco
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Receptor, Cannabinoid, CB2 ,HEK293 Cells ,Receptor, Cannabinoid, CB1 ,Alzheimer Disease ,Animals ,Humans ,Mice, Transgenic ,Microglia ,Cells, Cultured ,Receptors, G-Protein-Coupled - Abstract
GPR18, still considered an orphan receptor, may respond to endocannabinoids, whose canonical receptors are CB
- Published
- 2018
22. Structural analogues of the natural products magnolol and honokiol as potent allosteric potentiators of GABAA receptors
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Alexander Fuchs, Clara T. Schoeder, Roland Baur, Erwin Sigel, and Christa E. Müller
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Honokiol ,Patch-Clamp Techniques ,Stereochemistry ,Xenopus ,Clinical Biochemistry ,Allosteric regulation ,Pharmaceutical Science ,Pharmacology ,Biochemistry ,Lignans ,Structure-Activity Relationship ,chemistry.chemical_compound ,Allosteric Regulation ,Drug Discovery ,Animals ,Protein Isoforms ,Receptor ,Molecular Biology ,Biological Products ,Natural product ,GABAA receptor ,Biphenyl Compounds ,Organic Chemistry ,Potentiator ,Receptors, GABA-A ,Magnolol ,Biphenyl compound ,chemistry ,Oocytes ,Molecular Medicine ,Protein Binding - Abstract
Biphenylic compounds related to the natural products magnolol and 4'-O-methylhonokiol were synthesized, evaluated and optimized as positive allosteric modulators (PAMs) of GABA(A) receptors. The most efficacious compounds were the magnolol analog 5-ethyl-5'-hexylbiphenyl-2,2'-diol (45) and the honokiol analogs 4'-methoxy-5-propylbiphenyl-2-ol (61), 5-butyl-4'-methoxybiphenyl-2-ol (62) and 5-hexyl-4'-methoxybiphenyl-2-ol (64), which showed a most powerful potentiation of GABA-induced currents (up to 20-fold at a GABA concentration of 3μM). They were found not to interfere with the allosteric sites occupied by known allosteric modulators, such as benzodiazepines and N-arachidonoylglycerol. These new PAMs will be useful as pharmacological tools and may have therapeutic potential for mono-therapy, or in combination, for example, with GABA(A) receptor agonists.
- Published
- 2014
23. Structural characterization and pharmacological evaluation of the new synthetic cannabinoid CUMYL-PEGACLONE
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Lukas Mogler, Cornelius Hess, Jan Schäper, Christa E. Müller, Laura M. Huppertz, Clara T. Schoeder, Jan Patrick Steitz, Philippe Bisel, Folker Westphal, Verena Angerer, and Volker Auwärter
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Benzimidazole ,Cannabinoid receptor ,Indazoles ,Indoles ,Stereochemistry ,medicine.medical_treatment ,Pharmaceutical Science ,CHO Cells ,01 natural sciences ,Analytical Chemistry ,Designer Drugs ,Receptor, Cannabinoid, CB2 ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Cricetulus ,Receptor, Cannabinoid, CB1 ,Synthetic cannabinoids ,medicine ,Environmental Chemistry ,European market ,Animals ,Humans ,030216 legal & forensic medicine ,Spectroscopy ,Indole test ,Indazole ,Psychotropic Drugs ,Cannabinoids ,Illicit Drugs ,010401 analytical chemistry ,Cannabinoid Receptor Agonists ,0104 chemical sciences ,chemistry ,Benzimidazoles ,Cannabinoid ,medicine.drug - Abstract
The number of new psychoactive substances (NPS) that have emerged on the European market has been rapidly growing in the last years, with a particularly high number of new compounds from the group of synthetic cannabinoid receptor agonists. There have been various political efforts to control the trade and the use of NPS worldwide. In Germany, the ‘Act to control the distribution of new psychoactive substances’ (NpSG) came into force in November 2016. In this new Act two groups of substances were defined, the group ‘cannabimimetics/synthetic cannabinoids’ covering indole, indazole and benzimidazole core structures, and a second group named ‘compounds derived from 2-phenethylamine’. Shortly after, the first retailers of ‘herbal blends’ promoted new products allegedly not violating the German NpSG. We describe the identification and structural elucidation of one of the first synthetic cannabinoids not being covered by the NpSG, 5-pentyl-2-(2-phenylpropan-2-yl)-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one. For isolation of the substance a flash chromatography separation was applied. The structure elucidation was performed using gas chromatography-mass spectrometry (GC-MS), gas chromatography-solid state infrared spectroscopy (GC-sIR), liquid chromatography-electrospray ionization-quadrupole time of flight-mass spectrometry (LC-ESI-qToF-MS) and nuclear magnetic resonance (NMR) analysis. Additionally, binding affinity towards the cannabinoid receptors CB1 and CB2 and efficacy in a cAMP accumulation assay was measured, showing full agonistic activity and high potency at both receptors. The new compound bears a γ-carboline core structure circumventing the German NpSG and also the generic definitions in other national laws. As a semi-systematic name for 2-cumyl-5-pentyl-gamma-carbolin-1-one CUMYL-PEGACLONE is suggested.
- Published
- 2017
24. Modeling Immunity with Rosetta: Methods for Antibody and Antigen Design
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Samuel Schmitz, Marion F. Sauer, Georg Kuenze, Jens Meiler, Cristina Martina, Amandeep K. Sangha, Brian J. Bender, Bruno E. Correia, Shannon T. Smith, Diego del Alamo, Alican Gulsevin, Hope Woods, Pranav Kodali, Clara T. Schoeder, Benjamin K. Mueller, Nina G. Bozhanova, Jared Adolf-Bryfogle, Jonathan H. Sheehan, Alexander M. Sevy, Jessica A. Finn, Jaume Bonet, James E. Crowe, Rocco Moretti, William R. Schief, and Brennica Marlow
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Software suite ,biology ,Extramural ,Computer science ,Computational biology ,Biochemistry ,Models, Biological ,Antibodies ,Antigen ,Docking (molecular) ,Polysaccharides ,biology.protein ,From the Bench ,Antibody ,Antigens - Abstract
Structure-based antibody and antigen design has advanced greatly in recent years, due not only to the increasing availability of experimentally determined structures but also to improved computational methods for both prediction and design. Constant improvements in performance within the Rosetta software suite for biomolecular modeling have given rise to a greater breadth of structure prediction, including docking and design application cases for antibody and antigen modeling. Here, we present an overview of current protocols for antibody and antigen modeling using Rosetta and exemplify those by detailed tutorials originally developed for a Rosetta workshop at Vanderbilt University. These tutorials cover antibody structure prediction, docking, and design and antigen design strategies, including the addition of glycans in Rosetta. We expect that these materials will allow novice users to apply Rosetta in their own projects for modeling antibodies and antigens.
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