Research Fields
We are organic chemists who are interested in using supramoelcular chemistry at the interface of biology/medicine and material science.
Our research focuses on the development, synthesis and evaluation of new supramolecular systems which function in polar solvents and thus might have prospect for applications. Currently our work mainly involves ionic interactions as a key non-covalent bond. We have introduced guanidiniocarbonyl pyrroles as one of the most efficient oxoanion binding motifs known so far relying on H-bond assisted ion pair formation.
With the help of combinatorial approaches, we have used this binding motif to develop sensors for amino acids or highly efficient stereoselective receptors for oligopeptides. Currently, we are working on protein surface or DNA recognition. For example, tetravalent peptide ligands identified from the screening of a combinatorial library were shown to be highly efficient non-competitive enzyme inhibitors working by binding to the protein surface thus blocking the access to the active site. We also found a new class of DNA-binding molecules which function as very efficient artificial transfection vectors.
We are also interested in self-assembling zwitterions which form soft materials such as vesicles, polymers or monolayers in polar solvents and on surfaces. For example, recently we developed a supramolecular polymer based on a monomer with two orthogonal self-complementary binding sites using either metal-ligand or ionic interactions. In a hierarchical self-assembly process this molecule first forms ion paired dimers which can be polymerized by the addition of metal ions. Such system can also lead to the formation of pH-switchable gels.
Protein Recognition
Within the framework of the CRC 1093 "supramolecular chemistry on proteins" we develop new peptide-based supramolecular ligands for protein surface binding. To identify such ligands rational design ideas derived from known structural data of the target proteins combined with combinatorial approaches are used. Most often these compounds are multi-armed peptide based ligands with incorporated tailor-made artificial binding motifs such as our guanidiniocarbonyl pyrrole cation (GCP), a highly specific anion binder. Hence, we target mainly anionic binding sites on the proteins often combined with neighbouring hydrophobic or aromatic regions. The combination of charged as well as hydrophobic and/or aromatic interactions for protein (surface) binding has proven very useful in this context. For combinatorial variation of our ligands we currently mainly use dynamic combinatorial chemistry based on reversible acyl hydrazone formation between peptide acyl hydrazines as binding arms and oligo-aldehydes as scaffold. Using suitable screening assays and deconvolution strategies information on active hits within the dynamic library can be obtained. The thus identified ligands are then resynthesized and further studied in detail. For this we perform together with our cooperation partners in the CRC binding studies on the isolated proteins using techniques such as isothermal titration calorimetry (ITC), UV/Vis- and fluorescence polarization spectroscopy, nmr studies and Raman spectroscopy, respectively. Furthermore, assays based on cellular systems as available by the biological partners in the CRC are employed.
selected references:
Q. Wang, X. Shi, X. Zhu, M. Ehlers, J. Wu, C. Schmuck; A fluorescent light up probe as an inhibitor for intracellular b-tryptase. Chem. Commun. 2014, 50, 6120.
Q.-Q. Jiang, W. Sicking, M. Ehlers, C. Schmuck; Discovery of potent inhibitors of human β-tryptase from pre-equilibrated dynamic combinatorial libraries. Chem. Sci. 2015, 6, 1792.
J. Matic, F. Supljika, N. Tir, P. Piotrowski, C. Schmuck, M. Abramic, I. Piantanida, S. Tomic, Guanidiniocarbonylpyrrole-aryl conjugates as inhibitors of human dipeptidyl peptidase III: combined experimental and computational study, RSC Adv. 2016, 6, 83044.
K. Samanta, P. Jana, C. Hirschhäuser, C. Schmuck; Protein Surface Recognition by Synthetic Molecules, in Comprehensive Supramolecular Chemistry II (Editor: Andrew Wilson), Elsevier, 2017, in press.
D. Maity, C. Schmuck; Synthetic Receptors for Amino Acids and Peptides. In Synthetic Receptors for Biomolecules, Editor Bradley Smith, RSC Books 2017.
Modifying the Properties and Functions of Peptides by Artificial Supramolecular Binding Sites
Proteins and Peptides are one of the most important classes of biomolecules. They function as biocatalysts, are involved in signal transduction processes and fulfill structural roles. Their properties and functions critically depend on their amino acid sequence which controls both the folding of the peptides and provides chemically active functional groups as needed for binding of other molecules and catalysis. However, the chemical space and variety provided by the 21 proteinogenic amino acids is limited. The use of artificial amino acids with tailor-made functional groups in the side chain might open the way to obtain new peptides and proteins with new and hitherto unknown properties and functions.
In our current work we explore how the use of a tailor-made arginine mimetic, the guanidiniocarbonyl pyrrole cation (GCP), incorporated into peptides changes their properties. The GCP has superior binding affinity for oxoanions compared to both the guanidinium cation of arginine as well as the ammonium cation of lysine, the two amino acid based anion binding motifs used by Nature. At the same time the GCP is less basic but also more hydrophobic than arginine or lysine. All these aspects significantly change the properties of peptides which contain this supramolecular binding site. For example, we developed the smallest peptide based artificial gene transfection vector known until known. A simple tetrapeptide with four GCP-groups in the side chains is a nontoxic but highly efficient transfection vector. But also the folding and conformational properties of small GCP-containing oligopeptides are dramatically different from their natural counter parts. This lecture will highlight examples from our recent work in this field.
selected References:
P. Jana, M. Ehlers, E. Zellermann, K. Samanta, C. Schmuck; pH-Controlled Formation of a Stable b-Sheet and Amyloid-like Fibers from an Amphiphilic Peptide: The Importance of a Tailor-Made Binding Motif for Secondary Structure Formation. Angew. Chem. Int. Ed. 2016, 55, 15287
M. Li, M. Radic Stojkovoic, M. Ehlers, E. Zellermann, I. Piantanida, C. Schmuck, Use of an octapeptide - guanidiniocarbonylpyrrol conjugate for the formation of a supramolecular beta-helix which further self-assembles into pH responsive fibers, Angew. Chem. Int. Ed. 2016, 55, 13015-13018
M. Li, S. Schlesinger, S. K. Knauer, C. Schmuck*, Introduction of a tailor made anion receptor into the side chain of small peptides allows fine-tuning the thermodynamic signature of peptide–DNA binding; Org. Bio. Chem. 2016, 14, 8800-8803.
M. Li, M. Ehlers, S. Schlesiger, E. Zellermann, S. Knauer, C. Schmuck, Incorporation of a Non-Natural Arginine Analogue into a Cyclic Peptide Leads to Formation of Positively Charged Nanofibers Capable of Gene Transfection, Angew. Chem. Int. Ed. 2016, 55, 598-601.
M. Li, S. Schlesiger, S. K. Knauer, C. Schmuck; A tailor made specific anion binding motif in the side chain transforms a tetrapeptide into an efficient gene delivery vector. Angew. Chem. Int. Ed. 2015, 54, 2941-2944
Artificial Gene Transfection Vectors
Transfection is a process by which oligonucleotides (DNA or RNA) are delivered into living cells. This allows the synthesis of target proteins as well as their inhibition (gene silencing). However, oligonucleotides cannot cross the plasma membrane by themselves; therefore efficient carriers are needed for successful gene delivery. Recombinant viruses are among the earliest described vectors. Unfortunately, they have severe drawbacks such as toxicity and immunogenicity. In this regard, the development of non-viral transfection vectors has attracted increasing interests, and has become an important field of research. We have discovered that our tailor-made anion binding site, the guanidiniocarbonyl pyrrole cation (GCP) is highly efficient in inducing the formation of tightly compact polyplexes upon binding to ds-DNA. This polyplexes are efficiently taken up by cells via endocytosis. Hence GCP-containing ligands can be used as a new class of non-cytotoxic gene transfection vectors, which can reach efficiencies similar to the current gold standards PEI or lipofectamin. The presence of thze GCP-cation in these ligands is crucial; related ligands containing the natural analogues arginine or lysine do not lead to transfection.
selected references:
K. Samanta, P. Jana, S. Bäcker, S. K. Knauer, C. Schmuck*, Guanidiniocarbonyl Pyrole (GCP) Conjugated PAMAM-G2, a Highly Efficient Vector for Gene Delivery: The Importance of DNA Condensation; Chem. Commun, 2016, 52, 12446-12449.
M. Li, M. Ehlers, S. Schlesiger, E. Zellermann, S. Knauer, C. Schmuck,* Incorporation of a Non-Natural Arginine Analogue into a Cyclic Peptide Leads to Formation of Positively Charged Nanofibers Capable of Gene Transfection, Angew. Chem. Int. Ed. 2016, 55, 598-601; DOI: 10.1002/anie.201508714.
M. Li, S. Schlesinger, S. K. Knauer, C. Schmuck*, Introduction of a tailor made anion receptor into the side chain of small peptides allows fine-tuning the thermodynamic signature of peptide–DNA binding; Org. Bio. Chem. 2016, 14, 8800-8803; DOI: 10.1039/c6ob01584k.
M. Li, S. Schlesiger, S. K. Knauer, C. Schmuck;* A tailor made specific anion binding motif in the side chain transforms a tetrapeptide into an efficient gene delivery vector. Angew. Chem. Int. Ed. 2015, 54, 2941-2944; DOI: 10.1002/anie.201410429.
H. Y. Kuchelmeister, S. Karczewski, A. Gutschmidt, S. Knauer, C. Schmuck;* Utilizing Combinatorial Chemistry and Rational Design: Peptidic Tweezers with Nanomolar Affinity to DNA can be transformed into Efficient Vectors for Gene Delivery by Addition of a Lipophilic Tail. Angew. Chem. Int. Ed. 2013, 52,14016-14020; DOI: 10.1002/anie.201306929.
Supramolecular Ligands As Sensors For Biologial Targets
Molecular Recognition of biomolecules such as proteins or DNA is of utmost importance for numerous biological processes. Supramolecular ligands which specifically bind to such targets can help to better understand the fundamentals of these recognition events. Furthermore, these ligands might be able to modulate the biological unction of the target. Often molecular recognition of biological targets is based on ion-pair formation in combination with hydrophobic interactions. We use small, but tailor-made combinatorial libraries which are specifically designed and hence biased for a given biological target, to identify supramolecular ligands which can bind to charged hot spots on a protein surface or polyanions such as DNA or certain polysaccharides (e.g. heparin). Part of our ligand design involves also the use of a tailor-made anion binding site, the guanidiniocarbonyl pyrrole cation, which we devloped as a superior binding site for oxoanions such as carboxylates or phosphates. We have succesfully used this approach to identify supramolecular ligands which modulate protein-protein-interactions, which act as efficient gene transfection vectors or which can be used to monitor nucleic acids, proteins or polysaccharides even within cells.
selected references
D. Maity, M. Li, M. Ehlers, C. Schmuck*; A metal-free fluorescence turn-on molecular probe for detection of nucleoside triphosphates. Chem. Commun. 2017, 53, 208-211; DOI: 10.1039/c6cc08386b.
D. Maity, C. Schmuck*; Fluorescent Peptide Beacons for the Selective Ratiometric Detection of Heparin, Chem. Eur. J. 2016, 22, 13156-13161; DOI: 10.1002/chem.201602240.
D. Maity, J. J. Jiang, M. Ehlers, J. C. Wu, C. Schmuck,* A FRET-enabled molecular peptide beacon with a significant red shift for the ratiometric detection of nucleic acids; Chem. Commun. 2016, 52, 6134-6137; DOI: 10.1039/c6cc02138g.
M. Radic Stojkovic, P. Piotrowski, C. Schmuck, * I. Piantanida;* Short, rigid linker between pyrene and guanidiniocarbonyl-pyrrole induced new set of spectroscopic responses to ds-DNA secondary structure. Org. Biomol. Chem. 2015, 13, 1629-1633; DOI: 10.1039/c4ob02169j
L. Chen, J. Wu,* C. Schmuck, H. Tian;* A Switchable Peptide Sensor for Real-time Lysosomal Tracking, Chem.Commun. 2014, 50, 6443-6446; DOI: 10.1039/C4CC00670D.
Q. Wang, X. Shi, X. Zhu, M. Ehlers, J. Wu,* C. Schmuck;* A fluorescent light up probe as an inhibitor for intracellular b-tryptase. Chem. Commun. 2014, 50, 6120-6122; DOI:10.1039/C4CC02208D.
Self-Assembling Zwitterions as building blocks for switchable gels and polymers
Our research focuses on the development, synthesis and evaluation of new supramolecular systems which function in polar solvents and thus might have prospect for applications. Currently our work mainly involves ionic interactions as a key non-covalent bond. We have introduced guanidiniocarbonyl pyrroles as one of the most efficient oxoanion binding motifs known so far relying on H-bond assisted ion pair formation.
Combining a self-complementary zwitterion, that we developed in recent years, with metal-ligand binding sites (e.g. terpyridines, catechols, bipyridine) self-assembling molecules with two or more orthogonal interactions are obtained. Depending on the conditions (e.g. pH, presence/absence of metal ions, concentrations) different types of self-assembled aggregates are formed such as ion-paired dimers, metal-complexes, linear or three-dimensional polymers and gels. Such gels can be switched between gel state and solution by different stimuli such as pH, temperature or competing metal-binding ligands. Also conventional polymers such as polyethylene imine (PEI) can be functionalized with additional supramolecular binding sites to obtain hybrid materials which possess new and different properties relative to the original polymers.
selected references:
P. Jana, C. Schmuck*; A Novel pH-Switchable Hydrogel from Tripodal Based Triszwitterion with Dendritic Features for Dye Encapsulation, Chem. Eur. J. 2017,; 23, 320-326; DOI: 10.1002/chem.201601122.
K. Samanta, C. Schmuck*, Two-Component Self-Assembly: Hierarchical Formation of pH Switchable Supramolecular Polymers by π-π Induced Aggregation of Ion Pairs, Chem. Eur. J. 2016, 22, 15242-15247.
K. Samanta, C. Schmuck*, Two-component self-assembly of a Tetra-Guanidiniocarbonyl Pyrrole Cation and Na4EDTA: Formation of pH switchable supramolecular networks, Chem. Commun. 2015, 51, 16065-16067.
M. Fleischer, C. Schmuck;* Transforming polyethylenimine into a pH-switchable hydrogel by additional supramolecular interactions, Chem. Commun. 2014, 50, 10464-10467; DOI: 10.1039/c4cc03281k.
Y. Hisamatsu, S. Banerjee, M. B. Avinash, T. Govindaraju, C. Schmuck;* A Unique pH-Responsive Supramolecular Gel from a Novel Quadruple Zwitterion which Responds to both Acid and Base. Angew. Chem. Int. Ed. 2013, 52,12550-12554; DOI: 10.1002/anie.201306986.
M. T. Fenske, W. Meyer-Zaika, H.-G. Korth, H. Vieker, A. Turchanin, C. Schmuck*; Cooperative Self-Assembly of Discoid Dimers: Hierarchical Formation of Nanostructures with a pH Switch. J. Am. Chem. Soc. 2013, 135, 8342-8349; DOI: 10.1021/ja4025148.