Universität Bonn

Research Training Group RTG 2873 - University of Bonn

new modalities in medicinal chemistry

Focus of research

Different strategies will be employed to discover tools and drugs for novel types of drug targets. The research program focuses on 9 research projects from four core themes that are closely interconnected:

Project overview
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(I) Targeted protein degraders

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In this project area, targeted protein degraders such as molecular glues and PROTACs will be developed. The targeted protein degradation approach is expected to offer significant advantages over classical inhibition strategies by small molecules, including (i) a catalytic mode of action, (ii) avoidance of resistance due to up-regulation of the targeted protein of interest (POI), (iii) oncomitant inhibition of all possible functions (i.e. enzymatic, scaffolding, regulatory, etc.) of the target, and (iv) the possibility of addressing currently undruggable targets.

Targeted protein degraders are highly promising; thus, the development of new E3 ubiquitin ligase ligands and innovative synthetic platforms for the preparation of PROTACs is of utmost interest. Hence, Gütschow and Steinebach will focus on the discovery of improved cereblon (CRBN) ligands as building blocks for PROTACs (P1), while Hansen will embark on the solidphase synthesis of protein degrader libraries (P2)

(II) Macrocyclic natural product-derived drugsline

Macrocyclic drugs possess several beneficial properties that make them suitable to address „undruggable“ targets with extended, flat binding sites. They combine complex functional and stereochemical diversity in a conformationally pre-organized macrocyclic structure, which can result in reduced entropy cost during target binding compared to linear analogues, leading to high affinity and selectivity for their protein targets.

Despite being in a chemical space beyond the Ro5, macrocycles often exhibit physicochemical and pharmacokinetic properties, such as sufficiently high solubility, lipophilicity, metabolic stability and bioavailability, that are appropriate for therapeutic applications. Our focus will be on the development of new macrocyclic antibiotics.

Menche and A. Müller (P3) are aiming at the synthesis and elucidation of the mode of action of complex polyketide antibiotics. Crüsemann (P4) will conduct the first SAR study around a promising new cyclic depsipeptide.

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(III) Biopolymers as Tools and Drug

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Biomacromolecules such as peptides/proteins, carbohydrates (polyglycosides) and nucleic acid- (RNA-, DNA-, oligonucleotide-)based drugs and even cellular therapies represent an emerging class of drug modalities.

Progress in biotechnology and drug delivery have contributed significantly to overcome difficulties in producing or applying biomacromolecular drugs. We will focus on different classes of biomacromolecules. Bendas (P5) plans to study the effects of sulfopolysaccharides derived from heparin and non-glycosidic polymeric mimetics in an immuno-oncological context. Schneider and Weindl (P6) focus on cryptic host defense peptides (‘cryptides’) to illuminate new mechanistic details of the immunomodulatory and antibiotic effects of these host defense peptides and to guide the development of optimized synthetic analogues.

In project P7 Kostenis, one of the experts in G protein signaling, will develop selective tools to enable studying the roles G12/13 proteins, a so far poorly studied class of G proteins, and explore their potential as future drug targets.

(IV) Drug Conjugate

Antibody- and nanobody-drug conjugates (ADCs) have gained importance as new modalities for targeted therapies since they can reduce toxicity and improve therapeutic effects. Conjugates with other polymers, or drug hybrids, e.g. with macrocyclic compounds, can likewise improve targeting, inhibit degradation, and enhance biological activity. Conjugation of drug molecules with fluorescent dyes provides probes that are indispensable for fluorescence microscopy, for developing fluorescence-based assays, and have potential as future in vivo diagnostics or theranostics.

A further type of promising drug conjugates are photo-caged drugs that allow light-induced drug release with high spatial and temporal resolution. Mayer (P8) will investigate targeted T-cell activation through optimized aptamer-antigen conjugates. In this core area, techniques for the design and preparation of conjugated ligands will be explored and developed. Orphan receptors are a group of poorly studied GPCRs, for which the physiological agonist is still unknown or unconfirmed.

The Müller group has broad experience in the medicinal chemistry of orphan GPCRs. Project P9 will focus on GPR84, which is of high interest as a potential drug target in immunology, inflammation and cancer. The receptor is coupled to Gi and G12/13 proteins. Thus, it is related to P7 (Kostenis), and close collaboration is intended. Moreover, innovative and challenging structural biology, e.g. X-ray co-crystal structures, will be attempted aiming to obtain a precise basis for the design of optimized drug conjugates and to understand their molecular interactions.

Drugs Conjugate
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Technology Platforms

Technology Platforms (TP) of up-to-date, advanced and innovative methods in medicinal chemistry will assist all projects providing cutting-edge techniques, methods and instruments. These will also allow advanced education and training of the future generation of medicinal chemists. The platforms will be accessible to all RTG members, and support will be provided by the staff scientists. The TPs will comprise of:

TP1: PharmaCenter Bonn Compound Library

A professional compound library, established and directed by Christa Müller, currently comprises more than 35.000 proprietary small molecules (synthetic compounds and natural products), in addition to a unique collection of compound fragments. Several groups of the RTG (P1, P2, P3, P4, P5, P6) will contribute to the library or utilize it. The chemical space will be extended by “new modality-beyond Ro5 compounds”.

TP2 Aptamer Platform
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TP2: Center of Aptamer Research and Development (CARD)

The CARD, established and headed by Günter Mayer, represents a platform that enables the fully automatic generation of aptamers.

TP3: Structural Biology

A platform for protein expression (with S2 labs), purification, and ligand-target co-crystallization has been established by the group of Christa Müller. The aim is to obtain high resolution crystal structures and cryo-electron microscopy structures, supported by molecular modeling and docking studies powered by artificial intelligence (AI) and machine learning solutions. Within the past 3 years, the establishment of this platform has been implemented in the Department of Pharmaceutical & Medicinal Chemistry, resulting in the first X-ray structures of a G protein-coupled receptor crystallized in Bonn (see, e.g., Claff et al., Angewandte Chemie, 2022). Access to synchrotron and cryo-electron microscopy facilities is secured by collaboration partners. The molecular modeling group is supported by close interactions with the company BioSolveIT located in Bonn which offers complimentary informatics including AI support.

  • Website will be established soon

TP4: Joint Platform of Instruments and Techniques

Up-to-date instruments and techniques will be provided to the members of the entire RTG. All areas of modern medicinal chemistry will be covered:

         I.            Analytical  Chemistry:

NMR (up to 600 MHz), MS (including a triple quadrupole-linear ion trap MS instrument for highly sensitive quantitative analysis; MALDI imaging), and CE  instruments

       II.            Biophysical & Biochemical Assays:

Radioligand binding assays, fluorescence and bioluminescence resonance energy transfer (FRET, BRET) assays, surface plasmon resonance (SPR) assays, microscale thermophoresis (MST), isothermal titration calorimetry (ITC), dynamic mass redistribution (DMR), cellular dielectric spectroscopy (Cellkey), optical and impedance-based sensor platforms

     III.            Physicochemical Methods:

Modern HPLC methods (for solubility and lipophilicity measurements), prediction of  pharmacokinetic properties, residence time (binding kinetics), cell permeability and potential toxicity of new molecules.

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