Author: iso_METriC-876_1

Georg Winter obtained his PhD degree from the Medical University of Vienna, working on elucidating the mechanism of action of anti-neoplastic drugs under the supervision of Prof. Giulio Superti-Furga. He specialized on proteomics- as well as chemical genetics approaches to identify drug resistance mechanisms and synergistic drug combinations. He continued his training in chemical biology, working as a postdoctoral fellow with Dr. James Bradner the Dana Farber Cancer Institute/Harvard Medical School. Supported by an EMBO fellowship, he innovated the first generalizable pharmacologic solution to in vivo target protein degradation (Winter et al., Science 2015). He was recruited as a CeMM Principal Investigator in June 2016 where his research is now focused on using the unique molecular pharmacology of targeted protein degradation to understand and disrupt fundamental principles of transcription and gene control aberrantly regulated in human cancers. Georg Winter (co-) authored 35 manuscripts including publications in Science, Nature, Nature Chemical Biology, Nature Genetics, Elife and Molecular Cell. His interdisciplinary research lab consists of 6 Postdocs, 4 graduate students and 3 technical assistants trained in molecular biology, organic chemistry and computational biology, and is supported by several national and international grants and fellowships including an ERC Starting Grant. Dr. Winter’s contribution to the field of targeted protein degradation was acknowledged via multiple prices and awards, including the prestigious Eppendorf Award 2019 and the Elisabeth Lutz Award of the Austrian Academy of Sciences. 

(Photo kindly provided by @CeMM )

Abstract:

Identification and Characterization of novel molecular glue degraders

Topic:

Targeted protein degradation (TPD) is a new therapeutic modality based on drugs that destabilize proteins by inducing their proximity to E3 ubiquitin ligases. In this presentation, I will discuss how we develop phenotypic drug screens to find novel small molecule degraders that function as “molecular glues”. Molecular glues are of particular interest as they can degrade otherwise unligandable proteins by orchestrating direct interactions between target and ligase. I will describe a scalable strategy toward glue degrader discovery that is based on chemical screening in hyponeddylated cells, coupled to a multi-omics target deconvolution campaign. This approach led us to identify compounds that induce ubiquitination and degradation of cyclin K by prompting an interaction of CDK12–cyclin K with a CRL4B ligase complex. Notably, this interaction is independent of a dedicated substrate receptor, thus functionally segregating this mechanism from all described degraders. Collectively, our data outline a versatile and broadly applicable strategy to identify degraders with nonobvious mechanisms and thus empower future drug discovery efforts.

Dr Andreas Bender is a Reader for Molecular Informatics with the Centre for Molecular Science Informatics at the Department of Chemistry of the University of Cambridge, as well as an Associate Director for Computational Safety within Clinical Pharmacology & Safety Sciences (CPSS) at AstraZeneca. In his work, Andreas is involved with the integration and analysis of chemical and biological data from different sources, such as structural and bioactivity data, gene expression readouts, cellular imaging data, pathway information, etc. The computational analysis of this information is in his research then aimed at understanding phenotypic compound action – such as cellular readouts and organism-level effects – on a mechanistic level, predicting molecular properties related to both compound effiacy and toxicity, as well as e.g. compound repurposing. He received his PhD from the University of Cambridge and worked in the Lead Discovery Informatics group at Novartis in Cambridge/MA as well as at Leiden University in the Netherlands before his current post. 

Abstract:

Using Artificial Intelligence and Chemical and Biological Data for Drug Discovery: Opportunities and Pitfalls 

Topic:

While Artificial Intelligence (AI) had a profound impact on areas such as image and speech recognition, comparable advances in drug discovery are rare. In this contribution, we will firstly discuss in which ways chemical and biological data differs fundamentally from data available in other domains, both in its quantity and its underlying characteristics. Subsequently, case studies will be presented where the use of chemical and biological data, in combination with computational algorithms, has been successfully applied to questions related to compound mode of action, efficacy and safety. We will conclude by outlining what is needed in the future in order to advance the application of algorithms in the drug discovery field further, in particular with respect to the in vivo relevance of any predictions that are being made. 

Marco Di Antonio got his MSci in Chemistry in 2007 from Pavia University (Italy), which was followed by a PhD in Molecular Sciences in Padua University (Italy) under the supervision of Prof. Manlio Palumbo. After completion of his PhD, Marco moved to Cambridge University (UK) where he started as a Research Assistant in Shankar Balasubramanian group in 2011, working on novel G-quadruplex ligands to target selectively RNA vs DNA structures and selective cross-linking agents for G-quadruplex DNA. In 2015 Marco was promoted to Senior Research Associate at Cambridge University, where he continued working on the biological role of DNA G-quadruplex structures. In 2018, Marco was awarded a prestigious BBSRC David Phillips Fellowship to start his research group at Imperial College London (Chemistry Department), where he currently leads a research group of 10 people. Marco’s group is interested in developing novel chemical biology tools to interrogate the role of DNA secondary structure formation in human cells, with particular focus on Ageing and Cancer biology.

Abstract:

Single-molecule visualisation of DNA G-quadruplex formation in live cells.

Topic:

G-rich sequences can form alternative DNA secondary structures called G-quadruplexes (G4s).1 Substantial evidence now exists to support that formation of G4 structures is related to gene-expression and the case for targeting G4s for therapeutic intervention is getting stronger.1 Nevertheless, there is a need to devise additional approaches to study G4s in living cells to build further understanding on their actual biological relevance. The in-situ observation of G4-formation in living cells would provide evidence that goes beyond observations by immunostaining and ChIP-Seq. In my talk, I will describe a new G4-specific fluorescent probe (SiR-PyPDS) that has properties that enable single-molecule detection of G4s. We use SiR-PyPDS to achieve real-time detection of individual G4 structures in living cells. Live-cell single-molecule fluorescence imaging of G4s is carried out under conditions that use low concentrations of the G4-binding fluorescent probe (20 nM) that enabled us to providing informative measurements representative of the population of G4s in living cells without globally perturbing G4 formation and dynamics. Single-molecule fluorescence imaging and time-dependent chemical trapping of unfolded G4s in living cells by means of DMS treatment, revealed that G4s fluctuate between folded and unfolded states. We also demonstrated that G4-formation in live cells is cell-cycle dependent and inhibited by chemical inhibition of transcription and replication. The observation of single fluorescent probes binding to individual G4s provides a new experimental perspective on G4-formation and dynamics in living cells, which I will discuss during my talk. 

Alessio Ciulli holds the Personal Chair of Chemical Structural Biology at the School of Life Sciences, University of Dundee. Dr Ciulli’s laboratory has made important contributions to selective chemical intervention on protein-protein interactions targets and to the development of proteolysis-targeting chimeric molecules (PROTACs) as a viable strategy for targeted protein degradation. Amongst his most significant discoveries are the fragment-based design of ligands for the E3 ligase von Hippel-Lindau (VHL), and their use to design one of the first VHL-based PROTACs: the BET degrader MZ1. Dr Ciulli’s Lab later illuminated fundamental insights into PROTACs’ mechanism of action, solving the first crystal structure of a PROTAC ternary complex. Dr. Ciulli is also the scientific founder of Amphista therapeutics, a company that develops new protein degradation platforms. 

Before joining Dundee, Dr Ciulli was a group leader at the University of Cambridge, where he previously earned his PhD degree. Amongst his honours are the EFMC Prize for Young Medicinal Chemist in Academia, the RSC Capps Green Zomaya Award in medicinal computational chemistry, and election as Fellow of the Royal Society of Chemistry.  

CV: https://www.lifesci.dundee.ac.uk/groups/alessio-ciulli//about  

Abstract:

How PROTAC degraders work and why the ternary complex matters

Topic:

Degrader molecules (also known as PROTACs) recruit proteins to E3 ubiquitin ligases for targeted protein degradation. Formation of a ternary complex between the PROTAC, the ligase and the target leads to the tagging of the target protein by ubiquitination, and subsequent proteasomal degradation.  

In 2015, we disclosed MZ1, a potent BRD4 degrader made of our fragment-based designed VHL ligand, and a pan-BET inhibitor. Since then, my Lab has illuminated fundamental structural and biophysical understanding of PROTAC molecular recognition and mechanism of action, including solving the first crystal structure of a PROTAC ternary complex showing how MZ1 brings together VHL and its target protein BRD4. These fundamental insights into the mode of action provide guiding principles to rationally design degraders and other proximity-inducer modalities for translation chemical biology and drug discovery. 

Dr. Christoph Rademacher earned his BSc in Molecular Biotechnology and MSc in Molecular Life Scienceat the University of Lübeck. In 2009, Dr. Rademacher received his doctorate from the same University, where he performed studies under the supervision of Prof. Dr. Thomas Peters in the Department of Chemistry working on virus/carbohydrate interactions using NMR spectroscopy. He then underwent postdoctoral training with Prof. Dr. James C. Paulson at The Scripps Research Institute (USA) in the Department of Chemical Physiology, where he entered the field of glycoimmunology. In December 2011, Dr. Rademacher his appointed at the Max Planck Institute of Colloids and Interfaces in the Department of Biomolecular Systems, where he became Emmy-Noether Research Group Leader in June 2012. In 2017, Dr. Rademacher holds an ERC Starting Grant. In 2020 he was appointed full professor at the University of Vienna and the Max F. Perutz Laboratories. His research is focused on the development and application of novel molecular probes to understand the role of carbohydrates in immune cell regulation with a strong emphasis on molecular drug targeting. 

Abstract:

CARBOHYDRATE RECEPTOR LIGANDS ENABLE TARGETED DELIVERY TO IMMUNE CELLS

Topic:

Important aspects of life such as self/non-self-differentiation, cell adhesion and migration are mediated by mammalian receptors recognizing carbohydrate structures. In particular, these receptors expressed by cells of the innate immune system have open new applications in immune cell modulation as novel adjuvants or for cell specific targeting because of their restricted expression pattern. However, chemical probes that specifically address these receptors are sparse and carbohydrates as their natural ligands only offer limited affinity and specificity. Hence, we have utilized fragment-based ligand as well as rational design approaches to identify small molecules capable of binding to carbohydrate receptors with sufficient affinity and specificity to modulate the biological function of lectins.  

The challenges we are faced with originate from the inherent feature of carbohydrate recognition sites being rather flat and featureless. Moreover, these sites are often solvent exposed and highly hydrophilic, thus being less accessible for drug-like molecules. Fragment screening using several orthogonal methods such as NMR, SPR, and flow cytometry led to distinct hits followed by structure-activity relationship series. Hits were evolved into micromolar binders for targets from the mammalian as well as bacterial lectins. New compound classes were discovered to excellently suited for addressing Ca2+ coordinating lectins. Lessons learned about lectin structure and dynamics, as well as the development of chemical probes and their immune cell modulation will be covered in this presentation.

Mark Brönstrup studied Chemistry at the Philipps-Universität Marburg and at the Imperial College in London. In 1999 he received his doctorate from the Technical University Berlin in Organic Chemistry. After his graduation, he worked from 2000 to 2013 for Aventis, Sanofi-Aventis and Sanofi, complemented by a research sabbatical in 2003 at Harvard Medical School. There, he led the Natural Product Sciences with the goal of discovering leads from natural sources and optimising them to clinical candidates, and he dealt with translational research projects as a section head for Biomarkers & Diagnostics in the Diabetes Division, and a domain head for Biomarkers, Bioimaging & Biological Assays at Sanofi. Since December 2013, he heads the department Chemical Biology at the Helmholtz Centre for Infection Research. Additionally, he holds a Professorship (W3) at the Leibniz Universität Hannover. His research is focused on the discovery and the characterization of novel antibacterial and antiviral drugs.

Abstract:

Assault, Siege or Trojan Horse Strategy: Use of Natural Products to Fight Bacterial Infections

Topic:

Multidrug resistant bacterial pathogens have become a major health concern. Especially infections by gram-negative bacteria are challenging, since their complex cell membrane architecture strongly impedes the uptake of drugs. Because microbial natural products continue to be the prime source to tackle these issues, we have investigated natural products as the basis for novel antibiotic. 

A broad spectrum of gram-positive and gram-negative pathogens is addressed by cystobactamids, oligo-arylamids originally isolated from Cystobacter sp.. Our efforts to optimize the antibiotic properties of the cystobactamids by medicinal chemistry will be presented. 

Beyond a classic ‘assault’ of bacteria with such antibiotics, the conjugation of natural products to targeting functions has been beneficial to improve their drug properties. In the so-called Trojan Horse Strategy, antibiotics are conjugated to siderophores to hijack the bacterial siderophore transport system, and thereby enhance the intracellular accumulation of drugs. We synthesized novel artificial siderophores, characterized their transport and resistance mechanisms, and their efficacy when coupled to antibiotic natural products. Finally, we present a novel approach for the selective bacterial targeting and infection-triggered release of antibiotic conjugates in the alternative siege concept, using the lipopeptide colistin as the antibiotic effector.

Laura Steindler obtained her PhD degree from Tel Aviv University, Israel, on the topic of sponge-bacteria interactions. She then did a first post-doctoral fellowship on rhizosphere bacteria and the involvement of quorum sensing gene-regulation in plant-microbe interactions, in the laboratory of Dr. Venturi at ICGEB, Trieste. In her second post-doctorate, at the laboratory of Dr. Giovannoni (OSU, Oregon, USA) she worked on the marine SAR11 clade, which is the dominant marine bacterium, worldwide, and she deciphered, for the first time, the function of proteorhodopsin in these ecologically important microorganisms. In 2011 she started her own laboratory at University of Haifa, Israel, where she continues studying both sponge-microbe interactions as well as genomic adaptations of bacteria to nutrient deplete oceanic regions. Dr. Steindler is on the Editorial Board of Applied and Environmental Microbiology, and associate Editor in Frontiers in Microbiology. She is author of more than 40 peer-reviewed publications. Dr. Steindler has widely advanced the field of microbial sponge symbiosis and is considered an expert on symbiont genomics and transcriptomics, where she applies cutting-edge next-generation sequencing approaches and advanced bioinformatics.

Abstract:

Defining host-microbe interactions in a basal metazoan: the sponge.

Topic:

Laura’s abstract will be provided here soon.

Vito Ferro completed his PhD at the University of Western Australia. Following postdoctoral studies at the Carlsberg Laboratory (Denmark) and the University of British Columbia (Canada) he returned to Australia in 1996 to join the Australian biotechnology company Progen Pharmaceuticals Ltd where he spent 12 years in various positions, including Director of Drug Discovery.

He was involved in the development of two out of only four heparanase inhibitors to have reached the clinic, and led the medicinal chemistry team that discovered PG545 (pixatimod), a heparan sulfate mimetic with immunomodulatory activity. PG545 is currently in clinical trials in combination with nivolumab for patients with advanced cancers. Following a brief period at Queensland University of Technology as a Principal Research Fellow he moved to his current position in the School of Chemistry and Molecular Biosciences at the University of Queensland in 2010. His research interests are in carbohydrate chemistry and chemical biology/medicinal chemistry, with a focus on the synthesis of compounds to probe and/or inhibit carbohydrate-protein interactions involved in disease processes. Of particular interest is heparan sulfate (HS) and the development of HS mimetics as potential drugs for cancer, infectious diseases and lysosomal storage disorders.

Abstract:

Synthetic Heparan Sulfate Mimetics Potently Inhibit SARS-CoV-2 by Disrupting the Spike-ACE2 Interaction

Topic:

The cell surface polysaccharide heparan sulfate (HS) has recently been identified as a co-receptor with the ACE2 protein for recognition of the S1 spike protein on SARS-CoV2 virus, revealing an attractive new target for therapeutic intervention. Here we show that the HS mimetic drug candidate pixatimod binds directly to the SARS-CoV-2 spike protein receptor binding domain (S1-RBD), altering its conformation and destabilizing its structure. Molecular modelling identified a binding site overlapping with the ACE2 receptor site. Consistent with this, pixatimod inhibits binding of S1-RBD to ACE2-expressing cells and displays a direct mechanism of action by inhibiting binding of S1-RBD to human ACE2. Assays with four different clinical isolates of live SARS-CoV-2 virus show that pixatimod potently inhibits infection of Vero cells at doses well within its safe therapeutic dose range. In the transgenic hACE2 mouse model, pixatimod-treated animals showed a significant reduction in viral titers in nasal turbinates and in brain. This demonstration of potent anti-SARS-CoV-2 activity establishes that synthetic HS mimetics can target the HS-Spike protein-ACE2 axis. Together with other known activities of pixatimod our data provides a strong rationale for its further investigation as a potential multimodal therapeutic to address the COVID-19 pandemic.