From the ganglioside GQ1ba to glycomimetic antagonists of the myelin-associated glycoprotein (MAG)

The tetrasaccharide 4, a substructure of ganglioside GQ1bα, shows a remarkable affinity for the myelinassociated glycoprotein (MAG) and was therefore selected as starting point for a lead optimization program. In our search for structurally simplified and pharmacokinetically improved mimics of 4, antagonists with modifications of the core disaccharide Galβ(1-3)GalNAc, as well as the terminal α(2-3)- and the internal α(2-6)-linked neuraminic acid were synthesized and tested in target-based binding assays. Compared to the reference tetrasaccharide 4, the most potent antagonist 17 exhibits a 360-fold improved affinity. Furthermore, pharmacokinetic parameters such as stability in the cerebrospinal fluid, logD and permeation through the BBB indicate the drug-like properties of antagonist 17

Tetra- and Hexavalent Siglec-8 Ligands Modulate Immune Cell Activation

Carbohydrate-binding proteins are generally characterized by poor affinities for their natural glycan ligands, predominantly due to the shallow and solvent-exposed binding sites. To overcome this drawback, nature has exploited multivalency to strengthen the binding by establishing multiple interactions simultaneously. The development of oligovalent structures frequently proved to be successful, not only for proteins with multiple binding sites, but also for proteins that possess a single recognition domain. Herein we present the syntheses of a number of oligovalent ligands for Siglec-8, a monomeric I-type lectin found on eosinophils and mast cells, alongside the thermodynamic characterization of their binding. While the enthalpic contribution of each binding epitope was within a narrow range to that of the monomeric ligand, the entropy penalty increased steadily with growing valency. Additionally, we observed a successful agonistic binding of the tetra- and hexavalent and, to an even larger extent, multivalent ligands to Siglec-8 on immune cells and modulation of immune cell activation. Thus, triggering a biological effect is not restricted to multivalent ligands but could be induced by low oligovalent ligands as well, whereas a monovalent ligand, despite binding with similar affinity, showed an antagonistic effect

Therapeutic Peptides as Emerging Options to Restore Misguided Host Defence and Homeostasis: From Teaching to Concept to Clinic

Among the many molecular entities suitable for therapeutic use, peptides have emerged as a particularly attractive option for academic drug discovery and development. Their modular structure and extendibility, the availability of powerful and affordable screening platforms, and the relative ease-of-synthesis render therapeutic peptides highly approachable for teaching and research alike. With a strong focus on the therapeutic modulation of host defence pathways, including the complement and renin-angiotensin systems, the Molecular Pharmacy group at the University of Basel strongly relies on peptides to introduce students to practical aspects of modern drug design, to discover novel therapeutics for immune and inflammatory diseases, and to expand on options for the preclinical development of a promising drug class. Current projects reach from student-driven iterative design of peptidic angiotensin-converting enzyme inhibitors and the use of phage display technology to discover novel immune modulators to the development of protective peptide coatings for biomaterials and transplants and the structure-activity-relationship-guided optimization of therapeutic peptide drug candidates in late-stage clinical trials. Even at the current stage, peptides allow for a perfect circle between pharmaceutical research and education, and the recent spark of clinical applications for peptide-based drugs may only increase the value and relevance of this versatile drug class

Glycosyltransferases: An Efficient Tool for the Enzymatic Synthesis of Oligosaccharides and Derivatives as well as Mimetics Thereof

Research over the past two decades has uncovered numerous biological roles for carbohydrates, e.g. in cell adhesion processes, signal transduction, malignant transformation, or viral and bacterial cell-surface recognition. Carbohydrates and structural analogues thereof are therefore considered as potential new leads. Although the chemical synthesis of carbohydrates is well established, the preparation of particular oligosaccharides still remains a costly and cumbersome challenge. A complementary approach to the chemical synthesis is the use of enzymatic methods. The transfer of monosaccharide moieties to natural substrates, catalyzed by glycosyltransferases, exhibits excellent chemo-, regio- and stereoselectivity. In addition, enzymatic glycosylations permit the synthesis of carbohydrate derivatives and even carbohydrate mimetics. Our results reveal a remarkable synthetic potential of fucosyltransferases VI (EC 2.4.1.65) and III (EC 2.4.1.65), and ? (2?3)-sialyltransferase ST3Gal III (EC 2.4.99.6). Their use for the preparative synthesis of oligosaccharides and derivatives as well as mimetics thereof is demonstrated

Glycosyltransferases — An Efficient Tool for the Enzymatic Synthesis of Oligosaccharides and Derivatives as Well as Mimetics Thereof

Research over the past two decades has uncovered numerous biological roles for carbohydrates, e.g. in cell adhesion processes, signal transduction, malignant transformation, or viral and bacterial cell-surface recognition. Carbohydrates and structural analogues thereof are therefore considered as potential new leads. Although the chemical synthesis of carbohydrates is well established, the preparation of particular oligosaccharides still remains a costly and cumbersome challenge. A complementary approach to the chemical synthesis is the use of enzymatic methods. The transfer of monosaccharide moieties to natural substrates, catalyzed by glycosyltransferases, exhibits excellent chemo-, regio- and stereoselectivity. In addition, enzymatic glycosylations permit the synthesis of carbohydrate derivatives and even carbohydrate mimetics. Our results reveal a remarkable synthetic potential of fucosyltransferases VI (EC 2.4.1.65) and III (EC 2.4.1.65), and ? (2?3)-sialyltransferase ST3Gal III (EC 2.4.99.6). Their use for the preparative synthesis of oligosaccharides and derivatives as well as mimetics thereof is demonstrated

SIGLEC-4 (MAG) Antagonists: From the Natural Carbohydrate Epitope to Glycomimetics

Siglec-4, also known as myelin-associated glycoprotein (MAG), is a member of the siglec (sialic acid-binding immunoglobulin-like lectins) family. MAG binds with high preference to sialic acids α(2-3)-linked to D-galactose. Although the involvement and relevance of its sialic acid binding activity is still controversial, it could be demonstrated that interactions of MAG with sialylated gangliosides play an important role in axon stability and regeneration. In this article we describe in detail our current understanding of the biological role and the carbohydrate specificity of siglec-4. Furthermore, this review compiles the intensive research efforts leading from the identification of the minimal oligosaccharide binding epitope in gangliosides via micromolar oligosaccharide mimics to the development of small molecular weight and more drug-like sialic acid derivatives binding with low nanomolar affinities. Such compounds will be useful to elucidate MAG's biological functions, which are currently not fully understood

A Thorough Training in Modern Drug Design

The laboratory class Modern Drug Design at the Department of Pharmacy of the University of Basel offers the students a thorough training in modern drug design. First, antagonists for the Bradykinin B2 receptor are designed using state-of-the-art modelling techniques, followed by solid-phase synthesis of the most potent candidates identified in silico. Thereafter, their activity is determined by a fluorometric assay. By communicating the results to the next class of students, a feedback loop is completed, thereby allowing the design strategy to be improved

Minireview: Bacterial Sialyltransferases for Carbohydrate Synthesis

Sialylation catalyzed by sialyltransferases is one of the most interesting enzymatic glycosyl transfer reactions, since chemical sialylations usually give only low yields and lead to poor stereoselectivities. In the last decade, several bacterial sialyltransferases were identified and found to exhibit broader substrate specificity than their mammalian counterparts. This suggests the potential usefulness of bacterial sialyltransferases in chemo-enzymatic synthesis of natural and non-natural sialooligosaccharides

Prodruggability of Carbohydrates - Oral FimH Antagonists

The bacterial lectin FimH is a promising therapeutic target for the nonantibiotic prevention and treatment of urinary tract infections. In this communication, an ester prodrug approach is described to achieve oral bioavailability for FimH antagonists. By introducing short-chain acyl promoieties at the C-6 position of a biphenyl α- d -mannopyranoside, prodrugs with an excellent absorption potential were obtained. The human carboxylesterase 2 was identified as a main enzyme mediating rapid bioconversion to the active principle. Despite their propensity to hydrolysis within the enterocytes during absorption, these ester prodrugs present a considerable progress in the development of orally available FimH antagonists