Periodic Reporting for period 1 - GLYTUNES (A multidisciplinary training network for the bioinspired development of glycomimetics tuning the Siglec-Sialoglycan axis)
Reporting period: 2021-03-01 to 2023-02-28
The GLYTUNES program addresses the increasing demand for the development of new diagnostic and therapeutic strategies against infectious, cancer and autoimmune diseases in the biotech, healthcare and pharma sectors. To this aim, an interdisciplinary European-based training programme within an outstanding collaborative research environment has been established, guided by leaders in their respective research fields and in close association with EU industrial partners.
Glycoscience has become an essential part of modern molecular medicine in the fields of diagnostic and therapeutic strategies. Understanding the role of glycans and glycosylation in immunity is critical to better understand the etiology and the progression of relevant immune diseases.
Siglecs (sialic acid-binding immunoglobulin-like lectins) are a broad range of cell surface immunomodulatory receptors that selectively recognize sialylated glycans with unique, yet overlapping, specificities, acting as a negative regulator of immune system triggering tolerogenic or immunogenic responses. The past decade has witnessed an explosion of discoveries linking aberrant sialic acid–Siglec interactions to a broad spectrum of pathologies including infection, autoimmunity and cancer. The Siglecs–sialoglycan axis is, therefore, an emerging attractive therapeutic target to prevent or affect the course of several diseases The overarching objective of GLYTUNES is to provide new knowledge and high high-level multidisciplinary and multisectoral training in order to i) understand at the molecular and dynamic level how (aberrant) interactions between the immunomodulatory receptors Siglecs and their sialylated cognate ligands contribute to the etiology of immune-related diseases (infectious, cancer diseases), ii) how to tune this axis to provide new promising glycobiotechnological therapeutic approaches and opportunities by the rational design and development of glycomimetics aimed at fine-tuning the Siglec- glycan axis.
Glycoscience has become an essential part of modern molecular medicine in the fields of diagnostic and therapeutic strategies. Understanding the role of glycans and glycosylation in immunity is critical to better understand the etiology and the progression of relevant immune diseases.
Siglecs (sialic acid-binding immunoglobulin-like lectins) are a broad range of cell surface immunomodulatory receptors that selectively recognize sialylated glycans with unique, yet overlapping, specificities, acting as a negative regulator of immune system triggering tolerogenic or immunogenic responses. The past decade has witnessed an explosion of discoveries linking aberrant sialic acid–Siglec interactions to a broad spectrum of pathologies including infection, autoimmunity and cancer. The Siglecs–sialoglycan axis is, therefore, an emerging attractive therapeutic target to prevent or affect the course of several diseases The overarching objective of GLYTUNES is to provide new knowledge and high high-level multidisciplinary and multisectoral training in order to i) understand at the molecular and dynamic level how (aberrant) interactions between the immunomodulatory receptors Siglecs and their sialylated cognate ligands contribute to the etiology of immune-related diseases (infectious, cancer diseases), ii) how to tune this axis to provide new promising glycobiotechnological therapeutic approaches and opportunities by the rational design and development of glycomimetics aimed at fine-tuning the Siglec- glycan axis.
This ITN has recruited 14 early-stage researchers (ESRs) who have undertaken a range of training activities. This has included research development training and includes consortium wide training, bespoke personalised training packages and operational training, entrepreneurial, management and presentations skills and ethics training. Their research is conducted across four work packages: WP1 Production of endogenous and exogenous sialylated ligands for binding and immunological studies. Exogenous microbial glycoconjugates, namely cell envelope components such as Lipopolysaccharide, Capsular polysaccharides from human-associate bacteria (as Fusobacterium, Acinetobacter, Neisseria strains), targeting host Siglecs were isolated. Sialylated glycan ligand libraries were developed, using organic and enzymatic synthetic approaches. Full or fragmented endogenous ligands, including the sialylated cancer-associated CD24 and Cancer-IgG recombinantly produced, were isolated from mammalian cells; WP2 Depiction of 3D complexes. Recombinant expression of Siglecs (Siglec-7, 10, 8, 9, 3) and analysis of the molecular basis of recognition and binding of Siglecs to natural endogenous and exogenous substrates was performed, using structural biology techniques like NMR spectroscopy, X-ray crystallography, CryoEM, computational and biophysical approaches, to i) get a detailed molecular picture of the Siglecs-glycans complexes; analyse the energetics and thermodynamics of the molecular interactions; fast screen possible binders with respect to a specific target receptor. WP3 Immunological studies of Siglecs - sialoglycans systems: to understand the immune mechanisms and signaling pathways that govern the interaction between Siglecs and both endogenous and exogenous ligands. The impact of exogenous, synthetic, sialylated conjugates was tested using human antigen-presenting cells, and the analysis of released cytokines, as well as the expression of co-stimulatory surface-markers will indicate the capacity of these molecules to induce/regulate effective T-cells activation. WP4 Development of novel glycomimetics: drug-design, synthesis and binding properties. The design of novel glycomimetics was performed to modulate the activity of Siglecs under study.
We will take advantage of the pivotal information on the macromolecular Siglec-ligand complexes understudy, manipulation of the chemical information encoded in sugar structures (the sugar code) to control or alter the flow of information read-out by Siglecs upon binding with sialylated glycans
Each of the ESRs has an individual, personalized research project joint supervised by a multi-disciplinary cross-sector team of at least two supervisors. Each project has been designed to take full advantage of expertise, methodology and technology available within the consortium.
So far, structure, conformation, properties of exogenous and endogenous Siglecs ligands have been accomplished. Glycan libraries targeting Siglecs were isolated and purified from bacterial envelope components and from eukaryotic cells or synthetized. In parallel, Recombinant expression of Siglecs was performed and their biophysical and structural characterization accomplished. Structural biology was used to describe the 3D complexes. Immunological studies on Siglecs - glycan systems were performed to understand the immune mechanisms and signaling pathways that govern the interaction between Siglecs and sialylated glycans; and novel glycomimetics were designed and synthetized.
We will take advantage of the pivotal information on the macromolecular Siglec-ligand complexes understudy, manipulation of the chemical information encoded in sugar structures (the sugar code) to control or alter the flow of information read-out by Siglecs upon binding with sialylated glycans
Each of the ESRs has an individual, personalized research project joint supervised by a multi-disciplinary cross-sector team of at least two supervisors. Each project has been designed to take full advantage of expertise, methodology and technology available within the consortium.
So far, structure, conformation, properties of exogenous and endogenous Siglecs ligands have been accomplished. Glycan libraries targeting Siglecs were isolated and purified from bacterial envelope components and from eukaryotic cells or synthetized. In parallel, Recombinant expression of Siglecs was performed and their biophysical and structural characterization accomplished. Structural biology was used to describe the 3D complexes. Immunological studies on Siglecs - glycan systems were performed to understand the immune mechanisms and signaling pathways that govern the interaction between Siglecs and sialylated glycans; and novel glycomimetics were designed and synthetized.
The Siglecs–sialoglycan axis is an emerging attractive therapeutic target to prevent or affect the course of several diseases. This will be achieved through a research program designed with i) an optimal synergy between carbohydrate chemistry and immunology/microbiology research groups aimed at the exploration of novel concepts, mechanisms and compounds for the rational design and development of novel glycomimetic targeting the Siglec-sialic acid axis, ii) training 14 ESRs in all scientific, non-scientific and social aspects related to glycosciences and drug discovery processes.
GLYTUNES will address the challenge of understanding and exploiting the Siglecs-glycans cross-talk by harnessing the synergy of combining chemical to biological, biophysical, immunological research strategies. GLYTUNES represents an interdisciplinary research programme to deliver new insights on mechanisms governing exogenous and endogenous sialylated glycans recognition by Siglecs, and how this knowledge can be translated into novel diagnostics and therapeutics, in particular synthetic glycomimetics
GLYTUNES involves 7 academic partners and 4 companies from 7 European countries, combining world-class expertise in carbohydrate chemical and structural biology, drug design and computational chemistry, synthetic and medicinal chemistry, biophysics, biochemistry, glycoimmunology and molecular and medical microbiology.
GLYTUNES will train 14 ESRs in a highly integrated and collaborative environment, underpinned by extensive interactions between academic and industrial partners and by their experience in higher education, training and mentoring, and endowed with state-of-the art scientific and technical expertise and infrastructures. The ESRs will thus acquire scientific and transferable skills to make them highly competitive and new leaders in top EU academia and research institutions, healthcare and biotech job markets.
GLYTUNES will address the challenge of understanding and exploiting the Siglecs-glycans cross-talk by harnessing the synergy of combining chemical to biological, biophysical, immunological research strategies. GLYTUNES represents an interdisciplinary research programme to deliver new insights on mechanisms governing exogenous and endogenous sialylated glycans recognition by Siglecs, and how this knowledge can be translated into novel diagnostics and therapeutics, in particular synthetic glycomimetics
GLYTUNES involves 7 academic partners and 4 companies from 7 European countries, combining world-class expertise in carbohydrate chemical and structural biology, drug design and computational chemistry, synthetic and medicinal chemistry, biophysics, biochemistry, glycoimmunology and molecular and medical microbiology.
GLYTUNES will train 14 ESRs in a highly integrated and collaborative environment, underpinned by extensive interactions between academic and industrial partners and by their experience in higher education, training and mentoring, and endowed with state-of-the art scientific and technical expertise and infrastructures. The ESRs will thus acquire scientific and transferable skills to make them highly competitive and new leaders in top EU academia and research institutions, healthcare and biotech job markets.