A5041656502- Chemical Synthesis and Analysis
- X-ray Diffraction in Crystallography
- Receptor Mechanisms and Signaling
- Crystallization and Solubility Studies
- Monoclonal and Polyclonal Antibodies Research
- Pancreatic function and diabetes
- Innovative Microfluidic and Catalytic Techniques Innovation
- Neuropeptides and Animal Physiology
- Click Chemistry and Applications
- Advanced biosensing and bioanalysis techniques
- Photoreceptor and optogenetics research
- Biochemical and Structural Characterization
- Antimicrobial Peptides and Activities
- RNA Interference and Gene Delivery
- Diabetes Treatment and Management
- Crystallography and molecular interactions
- Glycosylation and Glycoproteins Research
- Lipid Membrane Structure and Behavior
- Mass Spectrometry Techniques and Applications
- Photochromic and Fluorescence Chemistry
- Computational Drug Discovery Methods
- Ubiquitin and proteasome pathways
- DNA and Nucleic Acid Chemistry
- RNA Research and Splicing
- Porphyrin and Phthalocyanine Chemistry
University of Zurich
2020-2025
Massachusetts Institute of Technology
2019-2024
Medical University of Vienna
2024
Ludwig-Maximilians-Universität München
2018-2023
ETH Zurich
2023
Center for Integrated Protein Science Munich
2018-2021
New York University
2019
Fully synthetic whole proteins in reach Solid-phase peptide synthesis of homogeneous peptides longer than about 50 amino acids has been a long-standing challenge because inefficient coupling and side reactions. Hartrampf et al. used an automated chemistry platform to optimize fast-flow were able produce fully single-domain (see the Perspective by Proulx). The targets included proinsulin enzymes such as barnase version HIV-1 protease containing multiple noncanonical acids. Refolded nearly...
Abstract High-diversity genetically-encoded combinatorial libraries (10 8 −10 13 members) are a rich source of peptide-based binding molecules, identified by affinity selection. Synthetic can access broader chemical space, but typically examine only ~ 10 6 compounds screening. Here we show that in-solution selection be interfaced with nano-liquid chromatography-tandem mass spectrometry peptide sequencing to identify binders from fully randomized synthetic members—a 100-fold gain in diversity...
Many peptidic natural products, such as lasso peptides, cyclic and cyclotides, are conformationally constrained show biological stability, making them attractive scaffolds for drug development. Although many peptides can be synthesized modified through chemical methods, knot-like microcin J25 (MccJ25) their analogues remain elusive. As the space of MccJ25 accessible purely methods is also limited, we proposed a hybrid approach: flow-based synthesis non-natural precursor followed by in vitro...
Abstract Rapid development of antisense therapies can enable on-demand responses to new viral pathogens and make personalized medicine for genetic diseases practical. Antisense phosphorodiamidate morpholino oligomers (PMOs) are promising candidates fill such a role, but their challenging synthesis limits widespread application. To rapidly prototype potential PMO drug candidates, we report fully automated flow-based oligonucleotide synthesizer. Our optimized platform reduces coupling times by...
The impermeable outer membrane of Pseudomonas aeruginosa is bypassed by antibacterial proteins known as S-type pyocins. Because their properties, pyocins are investigated a potential new class antimicrobials against infections. Their production and modification, however, remain challenging. To address this limitation, we employed automated fast-flow peptide synthesis for the rapid pyocin S2 import domain. N-terminal domain sequence (PyS2NTD) was synthesized in under 10 h purified to yield...
The glucagon-like peptide-1 receptor (GLP1R) is a broadly expressed target of peptide hormones with essential roles in energy and glucose homeostasis, as well the blockbuster weight-loss drugs semaglutide liraglutide. Despite its large clinical relevance, tools to investigate precise activation dynamics this high spatiotemporal resolution are limited. Here, we introduce novel genetically encoded sensor based on engineering circularly permuted green fluorescent protein into human GLP1R, named...
The chemical synthesis of polypeptides involves stepwise formation amide bonds on an immobilized solid support. high yields required for efficient incorporation each individual amino acid in the growing chain are often impacted by sequence-dependent events such as aggregation. Here, we apply deep learning over ultraviolet–visible (UV–vis) analytical data collected from 35 427 fluorenylmethyloxycarbonyl (Fmoc) deprotection reactions performed with automated fast-flow peptide synthesizer....
Orexin neuropeptides carry out important neuromodulatory functions in the brain, yet tools to precisely control activation of endogenous orexin signaling are lacking. Here, we developed a photocaged orexin-B (photo-OXB) through C-terminal photocaging strategy. We show that photo-OXB is unable activate its cognate receptors dark but releases functionally active native upon uncaging by illumination with UV-visible (UV-vis) light (370–405 nm). established an all-optical assay combining...
(+)-Stephadiamine is an unusual alkaloid isolated from the vine Stephania japonica. It features a norhasubanan skeleton, and contains two adjacent α-tertiary amines, which renders it attractive synthetic target. Here, we present first total synthesis of stephadiamine, hinges on efficient cascade reaction to implement aza[4.3.3]propellane core alkaloid. The α-aminolactone moiety in highly hindered position was installed via Tollens Curtius rearrangement. Useful building blocks for asymmetric...
Automated flow peptide synthesis (AFPS) gives access to peptides and proteins with post-translational modifications (PTMs) enables investigation of PTM-mediated regulation, was used study the PTM-dependence MYC:Bin1 interaction.
α-Galactosylceramides are glycosphingolipids that show promise in cancer immunotherapy. After presentation by CD1d, they activate natural killer T cells (NKT), which results the production of a variety pro-inflammatory and immunomodulatory cytokines. Herein, we report synthesis biological evaluation photochromic derivatives KRN-7000, activity can be modulated with light. Based on established structure–activity relationships, designed photoswitchable analogues this glycolipid control...
Antisense peptide nucleic acids (PNAs) have yet to translate the clinic because of poor cellular uptake, limited solubility, and rapid elimination. Cell-penetrating peptides (CPPs) covalently attached PNAs may facilitate clinical development by improving uptake into cells. We report an efficient technology that utilizes a fully automated fast-flow instrument manufacture CPP-conjugated (PPNAs) in single shot. The machine is rapid, with each amide bond being formed 10 s. Anti-IVS2-654 PPNA...
Abstract Glioblastoma (GBM) is the most common and deadliest form of brain tumor remains amongst difficult cancers to treat. Brevican (Bcan), a central nervous system (CNS)‐specific extracellular matrix protein, upregulated in high‐grade glioma cells, including GBM. A Bcan isoform lacking glycosylation, dg‐Bcan, found only GBM tissues. Here, dg‐Bcan explored as molecular target for In this study, d ‐peptide library screened identify small 8‐amino acid dg‐ B can‐ T argeting P eptide (BTP)...
Glioblastoma (GBM) is the most common and deadliest malignant primary brain tumor, contributing significant morbidity mortality among patients. As current standard-of-care demonstrates limited success, development of new efficacious GBM therapeutics urgently needed. Major challenges in advancing chemotherapy include poor bioavailability, lack tumor selectivity leading to undesired side effects, permeability across blood-brain barrier (BBB), extensive intratumoral heterogeneity. We have...
A new data analytical method for flow-based peptide synthesis enables robust and quantitative analysis of sequence-dependent difficult couplings.
Peptide aggregation is a long-standing challenge in chemical peptide synthesis, limiting its efficiency and reliability. Although data-driven methods have enhanced our understanding of many sequence-based phenomena, no comprehensive approach addresses so-called “non-random difficult couplings” (generally linked to aggregation) during solid-phase synthesis. Here, we leverage existing synthesis datasets, supplemented with newly acquired experimental data, build predictive model that deciphers...
Phosphorus-31 Nuclear Magnetic Resonance (31P-NMR) spectroscopy is a powerful technique for characterizing phosphorus-containing compounds in diverse chemical en- vironments. However, spectral interpretation remains time-consuming and expertise- dependent task, relying on reference tables empirical comparisons. In this study, we introduce data-driven approach that automates 31P-NMR analysis, pro- viding rapid accurate predictions of local phosphorus environments. By leveraging curated...
Structure elucidation is crucial for identifying unknown chemical compounds, yet traditional spectroscopic analysis remains labour-intensive and challenging, particularly when applied to a large number of spectra. Although machine learning models have successfully predicted structures from individual modalities, they typically fail integrate multiple modalities concurrently, as expert chemists usually do. Here, we introduce multimodal multitask transformer model capable accurately predicting...
Abstract Flow‐based approaches to solid phase peptide synthesis (SPPS) have been pursued since the method's early days, with anticipated gains in speed, reaction monitoring, and ease of automation. Here, we discuss how these advantages are being realized by at elevated temperature, facilitated a 'preheat/activation' loop. This important modification both accelerates synthesis—providing wealth new data from in‐line monitoring—and conjunction an optimized protocol, extends length peptides...
<p>Ribosomes produce most proteins of living cells in seconds. Here we report highly efficient chemistry matched with an automated fast-flow instrument for the direct manufacturing peptide chains up to 164 amino acids over 328 consecutive reactions. The machine is rapid - chain elongation complete hours. We demonstrate utility this approach by chemical synthesis nine different protein that represent enzymes, structural units, and regulatory factors. After purification folding,...
The glucagon-like peptide 1 receptor (GLP-1R) is a class B G-protein coupled (GPCR) and diabetes drug target expressed mainly in pancreatic β-cells that, when activated by its agonist (GLP-1) after meal, stimulates insulin secretion β-cell survival proliferation. N-terminal region of GLP-1 interacts with membrane-proximal residues GLP-1R, stabilizing active conformation to trigger intracellular signaling. best-studied peptides, exendin-4, share sequence homology at their region; however,...
Despite the generally accepted role of hydrophobic effect as driving force for folding, many intrinsically disordered proteins (IDPs), including those with content typical foldable proteins, behave nearly self-avoiding random walks (SARWs) under physiological conditions. Here, we tested how temperature and ionic conditions influence dimensions N-terminal domain pertactin (PNt), an IDP amino acid composition folded proteins. While PNt contracts somewhat temperature, it nevertheless remains...
Class-B1 G-protein-coupled receptors (GPCRs) are an important family of clinically relevant drug targets that remain difficult to investigate via high-throughput screening and in animal models. Here, we engineered PAClight1 P78A , a novel genetically encoded sensor based on class-B1 GPCR (the human PAC1 receptor, hmPAC1R) endowed with high dynamic range (Δ F / 0 = 1100%), excellent ligand selectivity, rapid activation kinetics ( τ ON 1.15 s). To showcase the utility this tool for vitro...