Glycosystems laboratory

The Glycosystems Laboratory is primarily dedicated to the in-depth study of molecular recognition processes of biological interest involving carbohydrates, as well as to the design of strategies to interfere with them. Specifically, through its various funded projects, the laboratory carries out:

• The synthesis of carbohydrates, glycoconjugates, and multivalent systems derived from them
• Their structural characterization using computational methods and Nuclear Magnetic Resonance (NMR) techniques
• The analysis of their interactions with the corresponding receptors through different techniques.

The ultimate goal of these studies is to gain a deeper understanding of the role of carbohydrates in these processes and to develop systems with potential applications in the fields of glycobiology and biomedicine.

Main research areas

1. Glycosaminoglycans: synthesis, structure and molecular recognition by protein receptors

Persons in charge: Pedro M. Nieto and José Luis de Paz

This research line is focused on the study of the role of glycosaminoglycans (GAGs) in some important biological processes, such as cell proliferation and pathogen infection. GAGs are negatively charged polysaccharides (mainly sulfated) that are crucial components of the extracellular matrix and cell surfaces. To decode the sulfation pattern responsible for a given activity, we synthesize GAG oligosaccharidic fragments as simple models of the natural polysaccharides. However, the chemical synthesis of these compounds is highly challenging and, for this reason, we also prepare non-GAG sulfated oligosaccharides that are synthetically more accessible and can mimic the structure and function of the natural products (glycomimetics).

The interactions between these synthetic derivatives and their protein receptors (for example, neuronal growth factors like midkine and pleiotrophin) are studied by using different techniques. Fluorescence polarization experiments afford relative binding affinity values with minimal time and sample consumption, allowing the identification of high affinity compounds with potential therapeutic applications. NMR and MD (molecular dynamics) yield a more structural view, allowing the proposal of 3D structures of the complex.

2. Glycoconjugates as tools to study interactions with lectins involved in the immune response.

Persons in charge: F. Javier Rojo and Javier Ramos-Soriano

This line of research focuses on the preparation of glycoconjugates or glycomimetics that enable a molecular-level understanding of interactions with lectins such as DC-SIGN, L-SIGN, Langerin, and others, which are present in specialized immune system cells. Within this framework, synthetic strategies are developed to access carbohydrates incorporating fluoro sugars, lanthanide-binding tags, deoxysugars, and other derivatives, which serve as synthetic tools to study carbohydrate–lectin interactions using different techniques such as NMR, biosensors, and more.

Furthermore, these glycoderivatives are conjugated onto different platforms (dendrimers, carbon nanostructures, etc.) to generate multivalent versions capable of effectively interacting with lectins. Such multivalent systems can induce internalization processes in antigen-presenting cells, thereby activate them, trigger specific signaling pathways, or inhibit infection processes. Therefore, these systems hold potential for use in the development of antivirals or vaccines with applications in biomedicine.

3. Structural NMR and MD of Glycans.

Person in charge: Pedro M. Nieto

This research line is common to the two previous ones. By means of NMR and MD, the determination of the 3D structures of the free ligands and the analysis of their dynamics is carried out, in order to characterize their intrinsic properties. When an unbalanced equilibrium exists between the free and bound ligand within the fast-exchange regime on the NMR timescale, we can apply a set of magnetization transfer-based NMR techniques to obtain information about the conformation of the ligand in the complex and to identify the ligand and receptor’s regions in closest contact. This approach allows us to assess whether the ligand undergoes conformational rearrangements upon binding, which is relevant since both binding and structural changes carry energetic consequences. Furthermore, STD (saturation transfer difference) experiments help to delineate the binding pocket, although a detailed definition requires extensive MD simulations.

We have mainly studied two types of systems: Growth Factors with GAG and C-Lectins with neutral saccharides.