A5022456945- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Peptidase Inhibition and Analysis
- Monoclonal and Polyclonal Antibodies Research
- Blood Coagulation and Thrombosis Mechanisms
- Protease and Inhibitor Mechanisms
- Chemical Synthesis and Analysis
- Advanced Proteomics Techniques and Applications
- Radiopharmaceutical Chemistry and Applications
- Signaling Pathways in Disease
- Cardiac Ischemia and Reperfusion
- Advanced Biosensing Techniques and Applications
- Ion-surface interactions and analysis
- Mast cells and histamine
- Cardiac Arrest and Resuscitation
- Cellular Mechanics and Interactions
- Medical Imaging Techniques and Applications
- Polymer Surface Interaction Studies
- Cardiovascular Function and Risk Factors
- Cardiac electrophysiology and arrhythmias
- Acute Myocardial Infarction Research
- Neuroendocrine Tumor Research Advances
- Prostate Cancer Treatment and Research
- Spectroscopy Techniques in Biomedical and Chemical Research
- Biochemical and Structural Characterization
- Cell Adhesion Molecules Research
Novo Nordisk (Denmark)
2022-2023
École Polytechnique Fédérale de Lausanne
2016-2021
AstraZeneca (Sweden)
2020
The rapid renal clearance of peptides in vivo limits this attractive platform for the treatment a broad range diseases that require prolonged drug half-lives. An intriguing approach extending peptide circulation times works through 'piggy-back' strategy which bind via ligand to long-lived serum protein albumin. In accordance with strategy, we developed an easily synthesized albumin-binding based on peptide-fatty acid chimera has high affinity human albumin (Kd=39 nM). This prolongs...
Inhibiting thrombosis without generating bleeding risks is a major challenge in medicine. A promising solution may be the inhibition of coagulation factor XII (FXII), because its knock-out or animals reduced causing abnormal bleeding. Herein, we have engineered macrocyclic peptide inhibitor activated FXII (FXIIa) with sub-nanomolar activity (Ki = 370 ± 40 pM) and high stability (t1/2 > 5 days plasma), allowing for preclinical evaluation first synthetic FXIIa inhibitor. This 1899 Da molecule,...
Blood contact with high surface area medical devices, such as dialysis and extracorporeal life support (ECLS), induces rapid coagulation. Systemic anticoagulation, heparin, is thus necessary to slow clot formation, but some patients suffer from bleeding complications. Both problems might be reduced by 1) replacing heparin anticoagulation artificial inhibition of the protein adsorption that initiates coagulation 2) selective intrinsic branch cascade. This approach was evaluated comparing...
Factor XII (FXII) is a plasma protease that has emerged in recent years as potential target to treat or prevent pathological thrombosis, inhibit contact activation extracorporeal circulation, and the swelling disorder hereditary angioedema. While several protein based inhibitors with high affinity for activated FXII (FXIIa) were developed, generation of small molecule been challenging. In this work, we have generated potent selective FXIIa inhibitor by optimizing peptide macrocycle was...
Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases at the intersection of health and disease due to their involvement in processes such as tissue repair immunity well cancer inflammation. Because high structural conservation catalytic domains shallow substrate binding sites, selective, small-molecule inhibitors MMPs have remained elusive. In a tour-de-force peptide engineering approach combining phage-display selections, rational design enhanced zinc chelation, d-amino acid...
Positron emission tomography (PET) imaging is used in drug development to noninvasively measure biodistribution and receptor occupancy. Ideally, PET tracers retain target binding properties of the investigated drug. Previously, we developed a zirconium-89 tracer based on long-circulating glucagon-like peptide 1 agonist (GLP-1RA) using desferrioxamine (DFO) as chelator. Here, aimed develop an improved zirconium-89-labeled GLP-1RA with increased molar activity increase uptake low density...
Cyclic peptides binding to targets of interest can be generated efficiently with powerful in vitro display techniques, such as phage or mRNA display. The cyclic peptide libraries screened these methods are by altering a combinatorial fashion the amino acid sequence peptides, number acids macrocycle rings, and cyclization chemistry. A structural element that cannot easily varied is backbone, which built from acids, each contributes three atoms macrocyclic ring structure. Here, we proposed...
Abstract Matrix metalloproteinases (MMPs) are zinc‐dependent endopeptidases at the intersection of health and disease due to their involvement in processes such as tissue repair immunity well cancer inflammation. Because high structural conservation catalytic domains shallow substrate binding sites, selective, small‐molecule inhibitors MMPs have remained elusive. In a tour‐de‐force peptide engineering approach combining phage‐display selections, rational design enhanced zinc chelation, d...
Positron emission tomography (PET) is a molecular imaging modality that enables non-invasive visualization of tracer distribution and pharmacology. Recently, peptides with long half-lives allowed once-a-week dosing glucagon-like peptide-1 receptor (GLP-1R) agonists therapeutic applications in diabetes obesity. PET for such long-lived hindered by the typically used short-lived radionuclides. Zirconium-89 (89Zr) emerged as promising radionuclide sufficiently half-life to be applied...
Actin is the most abundant protein in eukaryotic cells and key to many cellular functions. The filamentous form of actin (F-actin) can be studied with help natural products that specifically recognize it, as for example fluorophore-labeled probes bicyclic peptide phalloidin, but no synthetic exist monomeric (G-actin). Herein, we have panned a phage display library consisting more than 10 billion peptides against G-actin isolated binders low nanomolar affinity greater 1000-fold selectivity...
Actin is the most abundant protein in eukaryotic cells and key to many cellular functions. Natural products that specifically recognize filamentous form of actin (F-actin) such as bicyclic peptide phalloidin are important tools study widely applied for imaging cytoskeleton cells. Herein, we aimed at developing peptide-based affinity reagents selectively bind monomeric (G-actin), which synthetic probes not available. Panning a phage display library comprising more than trillion different...
Myocardial ischemia reperfusion (I/R) injury contributes to almost half of the necrotic area after myocardial infarction. To date there is no approved drug prevent or reduce I/R injury. The study and understanding pathophysiological mechanisms essential develop successful treatments. Large animal experiments are an important step in translational methods. porcine model acute infarction has been established described by ourselves others. We aimed further improve value focusing detail on...
Myocardial ischemia reperfusion (I/R) injury contributes to almost half of the necrotic area after myocardial infarction. To date there is no approved drug prevent or reduce I/R injury. The study and understanding pathophysiological mechanisms essential develop successful treatments. Large animal experiments are an important step in translational methods. porcine model acute infarction has been established described by ourselves others. We aimed further improve value focusing detail on...
<p>Actin is the most abundant protein in eukaryotic cells and key to many cellular functions. Natural products that specifically recognize filamentous form of actin (F-actin) such as bicyclic peptide phalloidin are important tools study widely applied for imaging cytoskeleton cells. Herein, we aimed at developing peptide-based affinity reagents selectively bind monomeric (G-actin), which synthetic probes not available. Panning a phage display library comprising more than trillion...