Periodic Reporting for period 2 - SWEETOOLS (Smart Biologics: Developing New Tools in Glycobiology)
Reporting period: 2017-08-01 to 2019-01-31
Sugars are ubiquitous molecules found throughout all kingdoms of life. Early studies contributed considerably to our appreciation of sugar functions by showing that abnormalities in the glycosylation can develop into pathogenesis and severe disease. Despite the crucial role of sugars in many biological events we still do not have adequate tools to decipher their complexity. To unveil the mysteries in the rapidly emerging field of sugar biology (glycobiology) we aim in this project to develop new tools that will help us to study and understand these important biomolecules. To realize this, we plan to construct unique bioconjugates, which will enable us to target various sugar processing enzymes with unprecedented selectivity. Our goal is to develop a new class of smart probes that will help us to answer fundamental questions in glycobiology. The outcomes of this project will significantly deepen our knowledge of glycoconjugates and in the long term, will allow for the design of efficient vaccines and for the development of better therapeutics.
Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far
In the first two prject periods, we have successfully started our work toward construction of highly selective glycosidase inhibitors. Numerous optimizations of synthetic procedures were performed to obtain the required compounds in sufficient amount and quality. First experiments devoted to the construction of glycopeptide libraries provided us with preliminary data. Based on our first results and experience, we have initiated alternative strategies which nicely complement the original ideas of the proposal. These include: construction of modified phage display libraries and alternative strategy for the development of efficient in situ click chemistry screening protocol as well as development of a new bottom-up approach for building more selective enzyme inhibitors. We are now able to construct the required phage display peptide libraries modified with the inhibitor. First screening results were initiated and we have successfully re-systhesized first hit peptide sequences. These data provided us with an important information on how these new type of systems behave and what is optimal/important to achieve good potency and selectivity of the peptide conjugates. We have also successfully developed a new synthetic approach enabling construction of heteroglycopeptide libraries. We are currently using this strategy and are performing first optimization experiment for screening using various lectins.
Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)
Our results are in good line with the outlined objectives. We believe that this project will deliver fundamentally new approach to study sugar processing enzymes, and as such, will provide us with valuable tools which could finally contribute to better treatment and diagnosis of various severe diseases.