A5068786003- Chemical Synthesis and Analysis
- Monoclonal and Polyclonal Antibodies Research
- Click Chemistry and Applications
- Advanced biosensing and bioanalysis techniques
- RNA and protein synthesis mechanisms
- Glycosylation and Glycoproteins Research
- Peptidase Inhibition and Analysis
- Biochemical and Structural Characterization
- Synthesis and Biological Evaluation
- Synthesis and Catalytic Reactions
- Angiogenesis and VEGF in Cancer
- Enzyme function and inhibition
- Protein Interaction Studies and Fluorescence Analysis
- Cell Adhesion Molecules Research
- Crystallization and Solubility Studies
- HER2/EGFR in Cancer Research
- X-ray Diffraction in Crystallography
- CAR-T cell therapy research
- Protein Degradation and Inhibitors
- melanin and skin pigmentation
- Synthetic Organic Chemistry Methods
- Crystallography and molecular interactions
- Asymmetric Synthesis and Catalysis
- Innovative Microfluidic and Catalytic Techniques Innovation
- Immune Cell Function and Interaction
ETH Zurich
2016-2025
École Polytechnique Fédérale de Lausanne
2003-2012
Philochem (Switzerland)
2010-2012
Queen Mary University of London
2002-2005
ConspectusDNA-encoded chemical libraries (DECLs) represent a promising tool in drug discovery. DECL technology allows the synthesis and screening of unprecedented size at moderate costs. In analogy to phage-display technology, where large antibody are displayed on surface filamentous phage genetically encoded genome, DECLs feature display individual small organic moieties DNA fragments serving as amplifiable identification barcodes. The DNA-tag facilitates simultaneous very sets compounds...
DNA encoding facilitates the construction and screening of large chemical libraries. Here, we describe general strategies for stepwise coupling coding fragments to nascent organic molecules throughout individual reaction steps as well first implementation high-throughput sequencing identification relative quantification library members. The methodology was exemplified in a DNA-encoded containing 4,000 compounds discovery binders streptavidin, matrix metalloproteinase 3, polyclonal human IgG.
Seeing eye to eye: Plasma-protein binding is effective in improving the pharmacokinetic properties of otherwise short-lived molecules. One compound a class small portable albumin binders can be used improve vivo circulatory half-life two widely contrast agents. It improves imaging performance fluorescein angiographic analysis retina mice (see picture). Supporting information for this article available on WWW under http://www.wiley-vch.de/contents/jc_2002/2008/z704936_s.pdf or from author....
DNA-encoded chemical libraries, i.e., collections of compounds individually coupled to distinctive DNA fragments serving as amplifiable identification barcodes, represent a new tool for the de novo discovery small molecule ligands target proteins pharmaceutical interest. Here, we describe design and synthesis novel library containing one million molecules. The was synthesized by combinatorial assembly three sets building blocks using Diels−Alder cycloadditions stepwise build-up barcodes....
New discoveries in RNA biology underscore a need for chemical tools to clarify their roles pathophysiological mechanisms. In certain cancers, synthesis of the let-7 microRNA tumor suppressor is blocked by an binding protein (RBP) Lin28, which docks onto conserved sequence precursor molecules and prevents maturation. Thus, Lin28/let-7 interaction might be attractive drug target, if not well-known difficulty targeting RNA-protein interactions with drugs. Here, we describe protein/RNA FRET...
Right on target: A chemically defined vascular-targeting antibody–drug conjugate (ADC) that offers comprehensive tumor coverage has been developed. When injected intravenously, this ADC potently inhibited growth in a syngeneic immunocompetent model of murine cancer which cannot be cured by conventional cytotoxic agents. Detailed facts importance to specialist readers are published as "Supporting Information". Such documents peer-reviewed, but not copy-edited or typeset. They made available...
Aldehyde drugs are gaining increasing research interest, considering that aldehyde dehydrogenases overexpression is characteristic of cancer stem cells. Here, we describe the traceless site-specific coupling a novel potent drug, containing an moiety, to recombinant antibodies, which were engineered display cysteine residue at their N-terminus, or 1,2-aminothiol C-terminus. The resulting chemically defined antibody-drug conjugates represent first example in thiazolidine linkage used for...
DNA-encoded combinatorial libraries are increasingly being used as tools for the discovery of small organic binding molecules to proteins biological or pharmaceutical interest. In majority cases, synthetic procedures formation incorporate at least one step amide bond between amino-modified DNA and a carboxylic acid. We investigated reaction conditions established methodology by using 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide, 1-hydroxy-7-azabenzotriazole N,N'-diisopropylethylamine...
Abstract Libraries of chemical compounds individually coupled to encoding DNA tags (DNA‐encoded libraries) hold promise facilitate exceptionally efficient ligand discovery. We constructed a high‐quality DNA‐encoded library comprising 30 000 drug‐like compounds; this was screened in 170 different affinity capture experiments. High‐throughput sequencing allowed the evaluation 120 million codes for systematic analysis selection strategies and statistically robust identification binding...
Abstract Methods for the rapid and inexpensive discovery of hit compounds are essential pharmaceutical research DNA‐encoded chemical libraries represent promising tools this purpose. We here report on design synthesis DAL‐100K, a library containing 103 200 structurally compact compounds. Affinity screening experiments DNA‐sequencing analysis provided ligands with nanomolar affinities to several proteins, including prostate‐specific membrane antigen tankyrase 1. Correlations sequence counts...
Maturing is easy to do: Annealing benzamidine–oligonucleotide conjugates with a library of DNA-encoded compounds allows the affinity capture pharmacophores that are capable binding exosites adjacent primary substrate-binding pocket serine protease trypsin. Selected show an improvement in IC50 values several orders magnitude compared starting benzamidine.
We describe the construction of a DNA-encoded chemical library comprising 148 135 members, generated through self-assembly two sub-libraries, containing 265 and 559 respectively. The was designed to contain building blocks potentially capable forming covalent interactions with target proteins. Selections performed JNK1, kinase conserved cysteine residue close ATP binding site, revealed preferential enrichment 2-phenoxynicotinic acid moiety (building block A82)...
Abstract The synthesis and characterization of a novel DNA‐encoded library macrocyclic peptide derivatives are described; the macrocycles based on three sets proteinogenic non‐proteinogenic amino acid building blocks featuring use copper(I)‐catalyzed alkyne‐azide cycloaddition (CuAAC) reaction for ring closure. (termed YO‐DEL) which contains 1 254 838 compounds, was encoded with DNA in single‐stranded format screened against target proteins interest using affinity capture procedures...
The first drugs discovered using DNA-encoded chemical library (DEL) screens have entered late-stage clinical development. However, DEL technology as a whole still suffers from poor purity resulting in suboptimal performance. In this work, we report technique to overcome issue through self-purifying release of the after magnetic bead-based synthesis. Both and last building blocks each assembled member were linked beads by tethers that could be cleaved mutually orthogonal chemistry. Sequential...