May 20th, 2021 by Katja Herzog
Felix Hausch is professor for structure-based drug research at the Technical University Darmstadt. He is a recognized expert for the chemical biology of immunophilins (mainly FKBPs) and has discovered the SAFit class of selective FKBP51 ligands. He has authored 82 publications (incl. Nat Chem Biol, Angew Chem, JACS; h-factor= 34 (Google Scholar)) and >10 accepted patent families. He is speaker of the LOEWE consortium TRABITA, Core team member of the Zukunftscluster PROXIDRUGS, coordinator of the BMBF consortia iMIP and 51TaValP, co-coordinator of the VIP+ consortium Fit4Fat and of the ANR/BMBF consortium SIAM. Felix Hausch received his PhD from the Free University Berlin in 2000, gained postdoc experience at Stanford University and biotech industry in Zurich (ESBATech AG, 2 years), and was group leader at the Max-Planck Institute of Psychiatry and lecturer at the LMU (Munich, 2005-2016).
Abstract:
De novo identification of a fully synthetic FKBP12-FRB Molecular Glue
Topic:
The gain-of-function pharmacology of Molecular Glues, prominently exemplified by the immunosuppressants FK506 and Rapamycin, holds great potential to address otherwise intractable targets. So far, the known Molecular Glues have been largely discovered by serendipity or in a target-agnostic manner. To explore the probability for the existence of Molecular Glues, we performed a targeted screen for Molecular Glues for FKBP12-FRB( FKBP-Rapamycin binding domain of mTOR), using Rapamcin as an established control. From our in-house FKBP-targeted ligand library, we identified a weak hit, that was validated in an FP-based secondary assay. Surprisingly, the structure of the ternary complex revealed a new binding mode of this hit compared to Rapamycin, which allow chemical optimization resulting in a fully synthetic FBKP12-FRB Molecular Glue with sub-micromolar efficacy. Our results show that with a focused library and a tailored assay cascade a targeted de-novo screening for Molecular Glues is feasible.
May 17th, 2021 by Katja Herzog
Alberto Dal Corso studied chemistry at Università degli Studi di Milano, where he obtained his Ph.D. in 2015 with Prof. Cesare Gennari. He then joined the group of Prof. Dario Neri at ETH Zürich as a postdoctoral fellow. In 2018, he returned to Università degli Studi di Milano, where he is currently working as a research fellow. In 2019 he was awarded the Junior Prize “Organic Chemistry for Life Sciences” by the Italian Chemical Society. His research interests include the development of novel drug delivery strategies and the synthesis of ligands for clinically relevant protein targets.
Abtract:
New-generation Self-Immolative Spacers for Fast and Controlled Release of Anticancer Drugs
Topic:
Self-immolative (SI) spacers are covalent constructs capable of undergoing a spontaneous disassembly starting from a stable and inactive state, in response to specific stimuli [1]. The growing interest in the generation of stimuli-responsive devices has led to the widespread application of SI spacers in different areas, including synthetic and analytical chemistry, material sciences, and medicinal chemistry, especially in the context of prodrugs, antibody-drug conjugates, and several other drug-release strategies. We have recently described a proline-derived SI spacer that is able to release different types of anticancer drugs (possessing either a phenolic or secondary and tertiary hydroxyl groups) through a fast cyclization mechanism involving carbamate cleavage. The high efficiency of drug release obtained with this spacer was found to be beneficial for the in vitro cytotoxic activity of protease-sensitive prodrugs, compared with a commonly used spacer of the same class. Starting from these findings, novel derivatives of this proline-derived SI spacer have been designed and synthesized, either to further accelerate the drug release rates or to develop a first-in-class spacer for dual-controlled drug release. These findings expand the repertoire of degradation machineries and are instrumental for the future development of highly efficient delivery platforms.
May 17th, 2021 by Katja Herzog
Riccardo Marin obtained his PhD in Chemistry jointly from the University Ca’ Foscari (Venice, Italy) and the Institut National de la
Recherche Scientifique (INRS – Varénnes, Canada) under the supervision of Prof. P. Canton and Prof. F. Vetrone. He then undertook a postdoctoral fellowship at the University of Ottawa from 2017 to 2019 with Prof. E. Hemmer and Prof. M. Murugesu. He is currently a Marie Skłodowska-Curie fellow at the Universidad Autónoma de Madrid in the group of Prof. D. Jaque. His research interests encompass the development and study of optically active (nano)materials based on lanthanide ions and semiconductors.
Topic:
Infrared-emitting multimodal nanostructures for controlled in vivo magnetic hyperthermia
Abstract:
Deliberate and local increase of the temperature within solid tumours represents an effective therapeutic approach. Thermal therapies embrace this concept leveraging the capability of some species to convert the absorbed energy into heat. To that end, magnetic hyperthermia (MHT) makes use of magnetic nanoparticles that can effectively dissipate the energy absorbed under alternating magnetic fields. Indeed, MHT is one of the very few nanoparticle-based therapeutic modalities that is currently clinical trial and that has therefore the potential to be used in the clinics. However, magnetic nanoparticles cannot provide realtime thermal feedback during MHT. As a result, unwanted overheating might occur and on-the-fly adjustment of the therapeutic parameters (such as the frequency of the alternating magnetic field) is unfeasible. Accurate, rapid, and cost-effective localization of magnetic nanoparticles within a tissue represents another challenge, which could increase the efficacy and precision of MHT. In this talk, I present the combination of iron oxide magnetic nanoparticles with state-of-the-art infrared luminescent nanothermometers (Ag2S nanoparticles) in a nanocapsule that simultaneously overcomes these limitations. The novel optomagnetic nanocapsule acts as multimodal contrast agent for different imaging techniques (magnetic resonance, photoacoustic, infrared fluorescence, optical tomography, and X-ray computed tomography). Most crucially, this nanocapsule
provides accurate (0.2 ⁰C resolution) and real-time subcutaneous thermal feedback during in vivo MHT, also enabling the attainment of thermal maps of the area of interest. These findings are a milestone on the road towards controlled magnetothermal therapies with minimal side effects.
May 17th, 2021 by Katja Herzog
Abstract:
A novel class of small molecule degraders targeting prion protein folding intermediate
Topic:
Decades of research efforts have conclusively provided overwhelming evidence that the cellular prion protein (PrPC) represents an optimal pharmaceutical target to tackle prion diseases, a set of fatal and incurable neurodegenerative disorders characterized by the conformational conversion of the physiological PrPC into a misfolded and infectious isoform referred to as PrP scrapie (PrPSc). Indeed, PrPC plays a key role in the disease etiology and knock-out experiments demonstrated that its therapeutic suppression can be considered safe. Over the years different strategies have been proposed to tackle this target based on traditional drug discovery approaches, such as the identification of small molecules able to promote the PrPC relocalization from cellular membrane to intracellular endosomes, as well as PrPC binders that prevent its conversion to PrPSc. However no therapy is yet available, and prion disease still represents a currently unmet medical need. Very recently, we have applied a novel drug discovery approach devoted to lowering PrPC levels by hampering a complete folding process. We refer to this strategy as Pharmacological Protein Inactivation by Folding Intermediate Targeting (PPI-FIT). The reconstruction of the PrP folding pathway through all-atoms MD simulation allowed the identification of a metastable intermediate of the PrP folding pathway characterized by a druggable pocket. Virtual screening of a commercial small molecule library resulted in the identification of thirteen potential binders, four of which capable of selectively lowering the load of PrP into the cellular membrane and promote its degradation. Additionally, one of these compounds inhibits prion replication in a dose-dependent fashion.
May 17th, 2021 by Katja Herzog
Dr. Albert Antolin obtained a PhD in Pharmacoinformatics (Pompeu Fabra University,Spain) pioneering the application of polypharmacology prediction to chemical biology by uncovering off-targets of chemical probes. Dr. Antolin was subsequently awarded a Marie Curie Fellowship to join the Institute of Cancer Research (UK) to develop the first objective resource for the assessment of chemical probes (https://probeminer.icr.ac.uk/). Next, Dr. Antolin won a Wellcome Fellowship to explore the polypharmacology of cancer drugs and their implications for precision oncology. Having worked in industry and academia, Dr. Antolin is interested in bridging industrial drug discovery with remaining fundamental questions in cancer chemical systems biology
Abstract:
From probe to drug: Polypharmacology across drug discovery
Topic:
Most small molecules interact with several target proteins but this polypharmacology is seldom comprehensively investigated or explicitly exploited during drug discovery. Here, we present the use of computational and experimental methods to identify and systematically characterize the kinase cross-pharmacology of representative HSP90 and PARP inhibitors. We demonstrate that the HSP90 inhibitors ganetespib and luminespib and the PARP inhibitors rucaparib and niraparib display unique off-target kinase pharmacology as compared to other clinical inhibitors of the same class, with important implications for personalized prescription. We also demonstrate that the early PARP chemical tool PJ34 displays a different polypharmacology than several FDA-approved PARP inhibitors, with important implications for target validation and the practise of chemical biology. We finally demonstrate that polypharmacology evolved during the optimisation to discover luminespib and that the hit, leads and clinical candidate all have different polypharmacological profiles. We therefore recommend the computational and experimental characterization of polypharmacology earlier in drug discovery projects to unlock new multi-target drug design opportunities as well as identifying undesired toxicity and unexplained cellular effects.
May 17th, 2021 by Katja Herzog
Topic:
Printing Biology: where printing meets synthetic biology
Abstract:
The assembly of life-like artificial systems is an emerging topic that contributes to the fundamental understanding of the molecular origins of life, and fuels the development of life-inspired platforms usable in different fields (e.g. molecular sensing, artificial biology, tissue engineering) [1]. The implementation of these platforms depends upon the ability to recapitulate the structural and functional features of biological systems, including multi-scale organization, adaptivity to environmental stimuli, collective behaviors [2]. The resulting research efforts have led to the recent definition of Printing Biology [3], a field resulting from the intersection between printing and the bottom up Synthetic Biology. Printing Biology aims at realizing reconfigurable multiscale systems (from nanometers to millimeters) with bespoke molecular composition, allowing for the determination of molecular interactions and features in conditions mimicking those of the living systems. As representative examples, the reproducible fabrication process of stable fL-scale compartments (the size selected by Nature for the formation of organelles and molecular condensates) by inkjet printing (IJP) and microcantilever spotting (μCS) will be shown.
The molecular composition of the compartments will be varied with the final aim to demonstrate the activity retention of different classes of the encapsulated biomolecules. Three different model applications will be shown, including DNA, proteins and phospholipids ink printable formulations. At first, the mechanism of DNA oligonucleotides ink imbibition by μCS into nylon porous supports is demonstrated (Figure 1). Subsequently, the immobilized DNA oligonucleotides (printed at different concentrations) are hybridized with a fluorolabeled complementary sequence permits to demonstrate the retaining of biological function [4], and the optical detection of oligonucleotides down to few tents of zeptomoles. As a second application, the retaining of CYP2E1 enzymatic activity from IJP compartments mimicking mitochondria is shown, highlighting the possibility to further induce spatial organization of the reaction products (Figure 2) [5]. Finally, preliminary experiments showing the realization of ordered phospholipids compartments containing fluorescein tagged phospholipids by μCS onto glass surfaces are reported. These systems allow for the realization of artificial platforms that could find applications in membrane-protein interaction studies.
May 17th, 2021 by Katja Herzog
Katarzyna Walczewska-Szewc is an assistant professor in the Theoretical Biophysics group, Nicolaus Copernicus University in Toruń, Poland. In her research she uses a number of computer-aided methods to model biomolecular interactions and to reveal the structural mechanisms of action of medically important proteins. She obtained her PhD degree in biology and physics jointly from the Australian National University and University of Gdansk, Poland. Katarzyna’s PhD project involved the development and use of numerical and simulation methods to design and interpret Förster resonance energy transfer (FRET) experiments in physics and biology
Abstract:
The changes in prolyl oligopeptidase structure upon inhibition modify its ability to decrease alpha-synuclein aggregation
Topic:
The formation of extended misfolded protein aggregates is one of the main reasons for neuronal malfunction and, eventually, brain damage in many neurodegenerative diseases. In Parkinson’s disease alpha-synucleins are implicated in the accumulation of the aggregates. The origin of such aggregation is not yet known, however, there is a compelling evidence that it can be reduced by inhibition of prolyl oligopeptidase (PREP). This effect cannot be simply related to the inhibition of the catalytic function of the enzyme, as not all PREP inhibitors stop the alpha-synuclein aggregation. Finding differences in the dynamics of the enzyme inhibited with diverse compounds would allow us to pinpoint the regions of the protein involved in the interaction between PREP and alpha-synuclein. Here, we study the action of three PREP inhibitors, each of which affects alphasynuclein aggregation to different extent. Using molecular dynamics modelling, we determine molecular mechanisms underlying the PREP inhibition and identify structural differences in each inhibitor-PREP system. We suggest that even subtle differences in the dynamics of the enzyme affect its interactions with alpha-synucleins. Thus, identification of these regions may be crucial in preventing formation of alpha-synuclein aggregates. Acknowledgement: The computational results were obtained using the facilities of the Interdisciplinary Centre for Modern Technologies, NCU, Poland
May 17th, 2021 by Katja Herzog
Abstract:
Immobilized Metal Affinity Chromatography as a Potential Drug Discovery Platform
Topic:
In 1990, approximately 80% of medicines approved in the U.S. were either natural products or their derivatives. In the early 2000s there was a significant drop in the number of natural products in clinical studies, coinciding with the expansion of high throughput screening (HTS) techniques. However, the limited structural diversity inherent to HTS and the emerging threat of antimicrobial resistance has reinvigorated the focus on exploiting natural products for the discovery and development of new medicines. Immobilized metal affinity chromatography (IMAC), a technique originally designed for the isolation of histidinetagged proteins, has shown promise in isolating and purifying bioactive compounds. IMAC relies on the fundamentals of coordination chemistry to reversibly retain compounds with known metal ion affinity. Although originally developed for recombinant protein purification, this simple method has been shown to readily purify hydroxamic acid siderophores, such as desferrioxamine B (DFOB) and other clinical agents, from bacterial cultures. Most IMAC work, in the context of siderophore isolation and purification, has utilized Ni(II) as the metal ion, but there is potential in substituting Ni(II) with other metal ions, such as Cu(II), Fe(III), Ga(III) and Zn(II). The modified IMAC resin beds may consequently act as metalloenzyme surrogates and select for different metabolites as directed by distinct coordination chemistries. This could open up a new platform to discover metalloenzyme inhibitor drug candidates as the isolated metabolites, by virtue of their metal binding affinity, may demonstrate activity against various metalloenzymes. As an initial proof of concept, we have exposed a mixture of in use metalloenzyme inhibitors to IMAC columns charged with various biologically relevant metals with promising results. The IMAC ligand-metal complex is a reasonable surrogate of the active site of a metalloenzyme and the method is capable of reversibly binding a variety of antihypertensive, anti-inflammatory and anticancer drugs.
May 17th, 2021 by Katja Herzog
Anna Hirsch researches primarily in the areas of antibiotics, structure-based virtual screening, energy-coupling factor transporter, multiparameter optimisation, and medicinal chemistry.
Abstract:
Discovery of antibacterial agents inhibiting the energy-coupling factor (ECF) transporters by structure-based virtual screening
Topic:
The emergence of antimicrobial resistance against important pathogens poses an ever-growing health threat. Hence, the pipeline of novel drug candidates should be filled with molecules featuring an unprecedented mode of action and a novel chemical structure. We tackle both challenges by targeting the Energy-coupling factor (ECF) transporter, an unexplored antibacterial target, mainly present in Gram-positive species. This family of transmembrane proteins is involved in the uptake of vitamins in a wide range of pathogenic bacteria (e.g., Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus faecium). Because of their central role in the metabolism of bacteria and their absence in humans, ECF transporters are novel attractive antimicrobial targets. Here, we report on the structure-based virtual screening (SBVS), design, synthesis and structure–activity relationships (SARs) of the first class of selective, antibacterial agents against the energy-coupling factor (ECF) transporters. Having identified a druggable pocket in the crystal structure of the L. delbrueckii ECF transporter, which should play a key role in the unique mechanism of transport, our SBVS of the zinc library afforded a fragment-like hit with good in vitro and cell-based activity, a good in vitro ADMET profile and excellent oral bioavailability. We adopted two distinct approaches, namely the design and synthesis of several derivatives according to a classical SAR approach and the screening of a focussed library of structurally related derivatives of our hit. Having established a new cell-based uptake assay in Lactobacillus casei, we identified a low-micromolar inhibitor of the ECF transporters with a broad spectrum of activity (MIC values in the single-digit micromolar range) and a lack of resistance development.
May 17th, 2021 by Katja Herzog
Abstract:
Morphological Profiling of Small Molecules for Mode-of-Action Prediction
Topic:
Profiling approaches monitor up to hundreds of parameters and are used to explore bioactivity of small molecules in an unbiased manner. The cell painting assay (CPA) is a morphology-based profiling that employs high-content imaging and analysis of six stained cellular components and compartments to extract hundreds of morphological features. Morphological fingerprints are used to assess bioactivity and are compared with fingerprints of annotated compounds with known target or activity. Profile similarity allows the generation of a target or mode-of-action hypothesis early on in the compound development process. We employed the cell painting assay to assess the bioactivity of our in-house compound collection. Detected activity can be mapped in the bioactivity cluster space and can be used to uncover unanticipated activity for reference compounds or to assign a mode of action to thus far unexplored small molecules .
