A5091780152- Monoclonal and Polyclonal Antibodies Research
- CAR-T cell therapy research
- Viral Infectious Diseases and Gene Expression in Insects
- CRISPR and Genetic Engineering
- Advanced biosensing and bioanalysis techniques
- Pancreatic function and diabetes
- Protein Degradation and Inhibitors
- RNA and protein synthesis mechanisms
- Click Chemistry and Applications
- RNA Interference and Gene Delivery
- Microbial Metabolic Engineering and Bioproduction
- Chemical Synthesis and Analysis
- Receptor Mechanisms and Signaling
- Pluripotent Stem Cells Research
- Biochemical and Structural Characterization
- Peptidase Inhibition and Analysis
- Molecular Junctions and Nanostructures
- Nanowire Synthesis and Applications
- Protein Structure and Dynamics
- DNA and Nucleic Acid Chemistry
- Advanced Glycation End Products research
- Coffee research and impacts
- bioluminescence and chemiluminescence research
- Transgenic Plants and Applications
- Immune Cell Function and Interaction
École Polytechnique Fédérale de Lausanne
2021-2025
SIB Swiss Institute of Bioinformatics
2021-2024
Bioengineering Center
2024
Bioengineering (Switzerland)
2024
ETH Zurich
2017-2023
München Klinik
1981
Molecular recognition events between proteins drive biological processes in living systems1. However, higher levels of mechanistic regulation have emerged, which protein–protein interactions are conditioned to small molecules2–5. Despite recent advances, computational tools for the design new chemically induced protein remained a challenging task field6,7. Here we present strategy that target neosurfaces, is, surfaces arising from protein–ligand complexes. To develop this strategy, leveraged...
Abstract Programming cellular behavior using trigger-inducible gene switches is integral to synthetic biology. Although significant progress has been achieved in trigger-induced transgene expression, side-effect-free remote control of transgenes continues challenge cell-based therapies. Here, utilizing a caffeine-binding single-domain antibody we establish caffeine-inducible protein dimerization system, enabling transcription factors and cell-surface receptors that enable expression response...
Tight control over protein degradation is a fundamental requirement for cells to respond rapidly various stimuli and adapt fluctuating environment. Here we develop versatile, easy-to-handle library of destabilizing tags (degrons) the precise regulation expression profiles in mammalian by modulating target half-lives predictable manner. Using well-established tetracycline gene-regulation system as model, show that dynamics can be tuned fusing appropriate degron gene regulators. Next, apply...
Abstract Rewiring cellular sensors to trigger non-natural responses is fundamental for therapeutic cell engineering. Current designs rely on engineered receptors that are limited single inputs, and often suffer from high leakiness low fold induction. Here, we present Generalized Engineered Activation Regulators (GEARs) overcome these limitations by being pathway-specific rather than input-specific. GEARs consist of the MS2 bacteriophage coat protein fused regulatory or transactivation...
Abstract Small-molecule responsive protein switches are crucial components to control synthetic cellular activities. However, the repertoire of small-molecule is insufficient for many applications, including those in translational spaces, where properties such as safety, immunogenicity, drug half-life, and side-effects critical. Here, we present a computational design strategy repurpose drug-inhibited protein-protein interactions OFF- ON-switches. The designed binders drug-receptors form...
Protein-based therapeutics, such as monoclonal antibodies and cytokines, are important therapies for various pathophysiological conditions oncology, autoimmune disorders, viral infections. However, the wide application of protein therapeutics is often hindered by dose-limiting toxicities adverse effects, namely, cytokine storm syndrome, organ failure, others. Therefore, spatiotemporal control activities these proteins crucial to further expand their application. Here, we report design...
Orthogonal tools for controlling protein function by post-translational modifications open up new possibilities circuit engineering in synthetic biology. Phosphoregulation is a key mechanism of signal processing all kingdoms life, but to control the involved processes are very limited. Here, we repurpose components bacterial two-component systems (TCSs) chemically induced phosphotransfer mammalian cells. TCSs most abundant multi-component signal-processing units bacteria, not found animal...
Abstract Cellular therapies remain constrained by the limited availability of sensors for disease markers. Here we present an integrated target-to-receptor pipeline constructing a customizable advanced modular bispecific extracellular receptor (AMBER) that combines our generalized molecule sensor (GEMS) system with high-throughput platform generating designed ankyrin repeat proteins (DARPins). For proof concept, chose human fibrin degradation products (FDPs) as markers high clinical...
Biological signal processing is vital for cellular function. Similar to electronic circuits, cells process signals via integrated mechanisms. In electronics, bandpass filters transmit frequencies with defined ranges, but protein-based counterparts controlled responses are lacking in engineered biological systems. Here, we rationally design protein-based, chemically responsive (CBPs) showing OFF-ON-OFF patterns that respond chemical concentrations within a specific range and reject outside...
Abstract Giant unilamellar lipid vesicles (GUVs) are widely used as model membrane systems and provide an excellent basis to construct artificial cells. To more sophisticated cells, proteins—in particular proteins—need be incorporated in GUVs. However, current methods for protein reconstitution have limited throughput or not generally applicable all proteins because they depend on detergent solubilization. This limitation is addressed here by introducing calcium‐mediated fusion transfer...
The ability to remotely control the activity of chimeric antigen receptors (CARs) with small molecules can improve safety and efficacy gene-modified T cells. Split ON- or OFF-switch CARs involve dissociation tumor-antigen binding from cell activation (i.e., CD3ζ) on receptor (R-) signaling (S-) chains, respectively, that either associate are disrupted in presence a molecule. Here, we have developed an inducible (i)ON-CAR comprising anti-apoptotic B lymphoma protein 2 ectodomain both chains...
Abstract Biological mechanisms that rely on signal integration and processing are fundamental for cell function. These types of capabilities analogous to those found in electronic circuits where individual components perform operations input signals. In electronics, bandpass filters crucial narrow frequencies within a specified range reject outside range. However, no generalizable protein-based currently available mimic such processes engineered biological systems, representing an unmet need...
We designed and engineered a dye production cassette encoding heterologous pathway, including human tyrosine hydroxylase Amanita muscaria 4,5-DOPA dioxygenase, for the biosynthesis of betaxanthin family plant fungal pigments in mammalian cells. The system does not impair cell viability, can be used as non-protein reporter to directly visualize dynamics gene expression by profiling absorbance or fluorescence supernatant cultures, well labeling individual Pigment also multiplexed with proteins...
Abstract Molecular recognition events between proteins drive biological processes in living systems. However, higher levels of mechanistic regulation have emerged, where protein-protein interactions are conditioned to small molecules. Here, we present a computational strategy for the design that target neosurfaces, i.e. surfaces arising from protein-ligand complexes. To do so, leveraged deep learning approach based on learned molecular surface representations and experimentally validated...
CAR T-cell therapy is constrained by on-target, off-tumor toxicities as well cellular exhaustion due to chronic antigen exposure. CARs comprising small-molecule controlled switches can enhance both safety and therapeutic efficacy but are limited the scarcity of non-immunogenic protein elements responsive non-immunosuppressive, clinically approved drugs with favorable pharmacodynamics. Here, we combine rational design library-based optimization a protein-protein interaction (PPI) human origin...
Abstract De novo protein design has enabled the creation of novel structures. To functional proteins, state-of-the-art approaches use natural proteins or first scaffolds that subsequently serve as templates for transplantation motifs. In these approaches, are function-agnostic and motifs have been limited to those with regular secondary structure. Here, we present a bottom-up approach build de tailored structurally complex We applied strategy four different binding motifs, including one...
Abstract Small-molecule responsive protein switches are crucial components to control synthetic cellular activities. However, the repertoire of small-molecule is insufficient for many applications, including those in translational spaces, where properties such as safety, immunogenicity, drug half-life, and side-effects critical. Here, we present a computational design strategy repurpose drug-inhibited protein-protein interactions OFF- ON-switches. The designed binders drug-receptors form...