Focus of research

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.

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.

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.