A5078759393- Chemical Synthesis and Analysis
- Receptor Mechanisms and Signaling
- Neuropeptides and Animal Physiology
- Click Chemistry and Applications
- Peptidase Inhibition and Analysis
- Monoclonal and Polyclonal Antibodies Research
- Synthetic Organic Chemistry Methods
- Synthesis and Biological Evaluation
- Sleep and Wakefulness Research
- Photochromic and Fluorescence Chemistry
- Cystic Fibrosis Research Advances
- Advanced biosensing and bioanalysis techniques
- Molecular Junctions and Nanostructures
- Synthesis and Catalytic Reactions
- Ion channel regulation and function
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Molecular spectroscopy and chirality
- Protease and Inhibitor Mechanisms
- Circadian rhythm and melatonin
- Ion Transport and Channel Regulation
- Virus-based gene therapy research
- Fluorine in Organic Chemistry
- Carbohydrate Chemistry and Synthesis
- Bacterial biofilms and quorum sensing
Friedrich-Alexander-Universität Erlangen-Nürnberg
2014-2025
Fischer (Germany)
2002-2021
University of Bayreuth
2010
Klinik und Poliklinik für Nuklearmedizin
2006
Klinikum rechts der Isar
2006
Innsbruck Medical University
2006
The cystic fibrosis transmembrane conductance regulator (CFTR) is a crucial ion channel whose loss of function leads to fibrosis, whereas its hyperactivation secretory diarrhea. Small molecules that improve CFTR folding (correctors) or (potentiators) are clinically available. However, the only potentiator, ivacaftor, has suboptimal pharmacokinetics and inhibitors have yet be developed. Here, we combine molecular docking, electrophysiology, cryo-EM, medicinal chemistry identify modulators. We...
Click for PET: An efficient strategy based on click chemistry has been developed 18F-labeling alkyne-bearing peptides with concomitant glycosylation. The mild conditions and general applicability of this reliable reaction gives access to a new class 18F-glycopeptide radiopharmaceuticals improved biological properties in vivo imaging studies by positron emission tomography (PET). Detailed facts importance specialist readers are published as "Supporting Information". Such documents...
Significance We custom synthesize a fluorescent ligand and use highly sensitive microscopy methods to show that receptors may be targeted distinct sites of cell. provide microscopic images the localization β 1 ‐adrenergic (β -ARs) 2 ‐ARs), main drivers contractility heart, in heart muscle cells. ‐ARs are exclusively specific structures these cells, T-tubules, while -ARs found at entire cell surface T-tubules. Such differential explain their different physiological functions, even though they...
The neurotensin receptor subtype 2 (NTS2) is involved in the modulation of tonic pain sensitivity and psychiatric diseases is, therefore, regarded as a highly attractive pharmacological target protein. Aiming to discover NTS2 selective ligands, we herein describe identification screening hits chemical synthesis structural variants leading potent peptide−peptoid hybrids type 3. mimetics 3a 3e−g incorporating an N-(4-hydroxyphenethyl)glycine substructure exhibit single digit nanomolar affinity...
3,4,5-Tri-O-acetyl-2-[18F]fluoro-2-deoxy-d-glucopyranosyl 1-phenylthiosulfonate (Ac3-[18F]FGlc-PTS) was developed as a thiol-reactive labeling reagent for the site-specific 18F-glycosylation of peptides. Taking advantage highly accessible 1,3,4,6-tetra-O-acetyl-2-deoxy-2-[18F]fluoroglucopyranose, three-step radiochemical pathway investigated and optimized, providing Ac3-[18F]FGlc-PTS in yield about 33% 90 min (decay-corrected based on starting [18F]fluoride). reacted with model pentapeptide...
A practical and efficient synthesis of spirobarbiturates type III is reported when NH acidity the imide function hydrophilic linker element allowed introduction different substituents. Structural characterization, which was based on both X-ray crystallography spectroscopic investigations, indicated II β-turn formation. Introduction molecular scaffold into solid phase peptide gave rise to spirocyclic neuropeptide analogs.
Derivatization of biologically active peptides by conjugation with fluorophores or radionuclide-bearing moieties is an effective and commonly used approach to prepare molecular tools diagnostic agents. Whereas lysine, cysteine, N-terminal amino acids have been mostly for peptide conjugation, we describe a new, widely applicable based on the nonclassical bioisosteric replacement guanidine group in arginine functionalized carbamoylguanidine moiety. Four arginine-containing receptor ligands...
The neurotensin (NT) receptor-1 (NTS1) is overexpressed in a variety of carcinomas and therefore an interesting target for imaging with positron emission tomography (PET). aim this study was the development new NT derivatives based on metabolically stable peptide sequence NLys-Lys-Pro-Tyr-Tle-Leu suitable PET imaging. peptides were synthesized by solid-phase supported synthesis elongated respective chelators (NODA-GA, DOTA) (68)Ga-labeling or propargylglycine (18)F-labeling via...
Members of the fungal kingdom serve as models for numerous cellular processes, among them sexuality.1 In heterothallic ascomycetes, mating-type systems ensure that only compatible isolates fuse to enter sexual phase.2,3,4,5,6 This includes reciprocal secretion and recognition pheromones, commonly termed α-factor a-factor, which are processed from peptide precursors.7,8,9,10 Identification mating pheromones their cognate receptors has been achieved by homology searches11,12,13,14,15,16,17;...
The development of privileged molecular scaffolds efficiently mimicking reverse turn motifs and thus increasing both binding selectivity enabling the elucidation bioactive conformation a natural peptide has attracted remarkable interest. frequent occurrence proline in various patterns initiated design proline-based mimetics. As structural hybridization highly potent type VI beta-turn inducer 1 with saturated spirocyclic lactams 3 II beta turns, we developed versatile synthetic route towards...
The neurotensin C-terminal hexapeptide, NT(8−13), which has been found to adopt a β-strand-like conformation while bound the NT1 receptor, was modified by introduction of conformational constraints. Synthesis four stereoisomeric 4.4-spirolactams 1−4 and subsequent receptor binding studies showed that restriction ψ(Pro10) approximately 130° leads more than 1000-fold increase affinity for 1 (Ki = 12 nM) when compared flexible analogue [NMeTyr11]NT(8−13).
Loss-of-function mutations of the epithelial sodium channel (ENaC) may contribute to pulmonary symptoms resembling those patients with atypical cystic fibrosis (CF). Recently, we identified a loss-of-function mutation in alpha-subunit ENaC (alphaF61L) an CF patient without CFTR. To investigate functional effect this mutation, expressed human wild-type alpha beta gamma-ENaC or mutant alpha(F61L) Xenopus laevis oocytes. The alphaF61L reduced mediated whole-cell currents by approximately 90%....
A small library of Fmoc-protected 3-arylated tyrosines was created by radical arylation. The new building blocks were successfully applied in the synthesis two novel neurotensin receptor ligands. Both isomers showed high affinity for human NTS2 with Ki values nanomolar range. Interestingly, subtype selectivity strongly depends on configuration peptide position 11. Isomer (11R)-3 displayed an excellent preference compared to NTS1.
In this work we report a design, synthesis, and detailed functional characterization of unique strongly biased allosteric agonists CXCR3 that contain tetrahydroisoquinoline carboxamide cores. Compound 11 (FAUC1036) is the first agonist selectively induces weak chemotaxis leads to receptor internalization β-arrestin 2 recruitment with potency comparable chemokine CXCL11 without any activation G proteins. A subtle structural change (addition methoxy group, 14 (FAUC1104)) led contrasting...
Proline-derived peptide mimetics have become an area of paramount importance in and protein chemistry. Since crystal structures frequently display Ψ angles 140−170° for prolyl moieties, our intention was to design a completely novel series 2,3-fused-proline-derived lactams covering this particular conformational space. Extending recently described toolset spirocyclic reverse-turn mimetics, we synthesized pyrrolidinyl-fused seven-, eight-, nine-membered unsaturated lactam model peptides...
The neurotensin receptor subtype 1 (NTS1) represents an attractive molecular target for imaging various tumors. Positron emission tomography (PET) gained widespread importance due to its sensitivity. We combined the design of a metabolically stable analogue with (68)Ga-radiolabeling approach. (68)Ga-labeled peptoid-peptide hybrid [(68)Ga]3 revealed high stability, specific tumor uptake (0.7%ID/g, 65 min p.i.), and advantageous biokinetics in vivo using HT29 tumor-bearing nude mice. Because...
The neurotensin receptor (NTS1) has emerged as an interesting target for molecular imaging and radiotherapy of NTS-positive tumors due to the overexpression in a range tumors. aim this study was develop 177Lu-labeled NTS1 radioligand, its application preclinical model therapy success by small-animal positron emission tomography (µPET) using [68Ga]DOTA-RGD specific tracer angiogenesis. peptide subjected studies on HT29-tumor-bearing nude mice vivo, defining four groups animals (single dose,...
Neurotensin receptor 1 (NTS1) is overexpressed on a variety of cancer entities; for example, prostate cancer, ductal pancreatic adenocarcinoma, and breast cancer. Therefore, it represents an interesting target the diagnosis these cancers types by positron emission tomography (PET) [...]
The epithelial sodium channel (ENaC) is essential for mediating absorption in several epithelia. Its impaired function leads to severe disorders, including pseudohypoaldosteronism type 1 and respiratory distress. Therefore, pharmacological ENaC activators have potential therapeutic implications. Previously, a small molecule activator (S3969) was developed. So far, little known about molecular mechanisms involved S3969-mediated stimulation. Here, we identified an S3969 binding site human by...
Molecular imaging using positron emission tomography (PET) can serve as a promising tool for visualizing biological targets in the brain. Insights into expression pattern and vivo of G protein-coupled orexin receptors OX1R OX2R will further our understanding system its role various physiological pathophysiological processes. Guided by crystal structures lead compound JH112 approved hypnotic drug suvorexant bound to OX2R, respectively, we herein describe design synthesis two novel...
Molecular imaging using positron emission tomography (PET) can serve as a promising tool for visualizing biological targets in the brain. Insights into expression pattern and vivo of G protein-coupled orexin receptors OX1R OX2R will further our understanding system its role various physiological pathophysiological processes. Guided by crystal structures lead compound JH112 approved hypnotic drug suvorexant bound to OX2R, respectively, we herein describe design synthesis two novel...