GLYCOPHARM · The Sugar Code: from (bio)chemical concept to clinics

The Sugar Code: from (bio)chemical concept to clinics

Coding of bioinformation in glycans and information transfer via lectins, i.e. the Sugar Code, are key to a wealth of medically relevant processes, as e.g. infection, immune regulation or malignancy. The GLYCOPHARM Marie Curie Initial Training Network was devised to offer training to young researchers in the interdisciplinary field of glycosciences, covering different aspects of the drug design and development processes. The main goal was to provide young researchers with broad scientific, entrepreneurial and transferable competences for optimizing their career perspectives. A key element was training through individual inter-disciplinary research projects, encompassing continuous transfer of scientific knowledge, know-how, and research methodologies and skills. All individual research projects focused on a family of human lectins that have emerged as potent regulators of adhesion and growth, the galectins. Combined the individual research projects covered the entire research programme, whose long-term goal was the development of galectin-targeted diagnostic and therapeutic strategies. Towards this aim, novel computational and NMR-based approaches have been developed for the screening of galectin ligands, analysis of ligand conformation, and detailed characterization, at atomic level, of galectin-ligand interactions. These approaches have helped to the design of new galectin-targeted compounds as potential inhibitors/modulators of the processes in which galectins are involved. Different saccharide libraries of application in these studies, as well as compounds newly designed based on computational predictions, were synthesized using established and novel synthetic routes. The new computational and NMR methodologies have also been successfully applied to other systems, beyond galectins, demonstrating their usefulness for speeding up early stages in the development of drugs targeted to carbohydrate receptors. New galectins and galectin-related proteins, also including natural and engineered variants as well as hybrid constructs, have been produced. The biophysical properties and biological activity of these proteins was thoroughly examined using a variety of techniques, and the structure of many of them was solved by X-ray crystallography, facilitating the establishment of structure-activity correlations. A novel hydrogen-deuterium exchange mass spectrometry approach was also developed to this aim. Of note, the first analysis of the complete galectin network in one organism was achieved, helping to unravel the functional significance of the occurrence of different members of this lectin family. The expression of galectins and galectin ligands in normal and pathological tissues, with main focus on cancer, has been analysed. In most cases, non-redundant expression profiles were observed, pointing at functional divergences. Upregulation of certain galectins was found to be associated with osteoarthritis and the severity of degeneration. In addition, the expression profile of galectins in keratitis-damaged corneas was found to be similar to that observed in stroma of squamous/basal skin cancer. Analysis of the expression of genes coding for galectins in samples from patients of squamous head and neck cancer revealed a tendency to differential expression patterns in carcinoma, tissue surrounding the carcinoma, and healthy tissue, encouraging further analyses for the establishment of clinical correlations. The role of tumour stroma in the progression of squamous head and neck cancer has been investigated, revealing that cancer-associated fibroblasts originate from local mesenchymal cells, and that tailor-made polyamines can inhibit their formation. The cancer microenvironment was discovered to be very similar to the microenvironment of the wound in the process of healing, what could be of application in regenerative medicine. The biological activity and effector properties of galectins in different physiological and pathological processes, as neuritogenesis, osteoarthritis, and colon carcinoma, were examined. The results have opened new perspectives for the regulation of these processes, with obvious clinical implications. Other results of the project that deserve to be highlighted include the detection of anti-galectin antibodies in neurological disorders using synthetic galectin peptides, of potential application in the development of new diagnostic tools, and the establishment of a yeast HTP platform for in vivo testing of compounds targeting Ras/KRAS and galectin-3 before using cancer cell lines or animal models, thus providing a front guard for pharmacological drug testing. On the whole, the scientific results of the project are expected to facilitate the development of pioneering strategies for fighting common diseases, with main focus on cancer. The socio-economic impact of these results was evidenced by the massive attention attracted from the media and the general public by the network partner from the 1st Faculty of Medicine of the Charles University of Prague upon discovery of possible new strategies for biological treatment of squamous-cell carcinoma of the head and neck. Besides scientific breakthroughs, the training programme has brought forth a rich offer of courses, workshops and seminars, imparted at biannual network meetings, which were accessible to researchers inside and outside the network. In addition, two summer schools were organized in collaboration with other Initial Training Networks, offering training in methodologies and approaches of application in biomedicine and (bio)technology, with focus on nanosciences, and in different aspects of the glycobiology field, beyond those explicitly included in the GLYCOPHARM programme. These and other GLYCOPHARM activities also served to establish and promote inter-ITN connections. Overall, the GLYCOPHARM programme has contributed to the development of a new generation of researchers, shaped according to modern society needs and able to associate research competences with the skills required for exploitation of their expertise in both academia and industry. Thus, the results of the project are relevant for a variety of target groups, including i) the researchers trained within the network, as continuing users of the training packages generated during the project and disseminators of the project activities and results, ii) the academic community, as potential users of the knowledge gained and teaching resources generated for improving education and training programs, and also for identifying new research challenges for future MSc and PhD projects, iii) the scientific community, as potential users of the knowledge, methodologies and platforms developed, iv) public/private sectors, as potential employers of the newly trained human resources, v) private companies, as potential users of newly developed products/technologies, and vi) the general public, as final beneficiaries of novel diagnostic and therapeutic strategies. To maximize the visibility and impact of the project activities and results, these have been continuously disseminated through the GLYCOPHARM website (www.glycopharm.eu) as well as quarterly newsletters distributed electronically and also posted in the website, available for download. The eye-catching corporate design is based on the project logo, a pyranose ring with a snake twined around it, evocative of the Hygieia's symbol, straightforwardly revealing the essence of GLYCOPHARM. Coordinator: Dolores Solís Agencia Estatal Consejo Superior de Investigaciones Científicas (CSIC) E-mail: d.solis@iqfr.csic.es

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