Project description
Targeted protein degradation for Golgi-resident enzymes
Oligosaccharides and glycoconjugates are vital biomolecules in health and disease, with carbohydrate metabolism relying on enzymes. Targeted protein degradation (TPD) technologies have the ability to degrade disease-related proteins, but they do not currently target proteins in the Golgi apparatus. Developing TPD strategies for Golgi-resident enzymes could help address unmet needs in diseases related to carbohydrate processing enzymes (CPEs). The ERC-funded SWEET DEGRADATION project will develop strategies for targeted degradation of proteins in the Golgi apparatus. It will develop molecules, termed GolgiTACs, which link CPEs (cargo proteins) to Golgi transporters, enabling their transport to lysosomes for degradation. These GolgiTACs will ultimately be evaluated in disease models, including lysosomal storage disorders and cancer, paving the way for new therapeutic approaches.
Objective
Oligosaccharides and glycoconjugates, a hugely diverse class of biomolecules, are closely associated with health and many diseases. Carbohydrate metabolism relies mainly on glycosidases and glycosyltransferases which are carbohydrate processing enzymes (CPEs) that break and create glycosidic bonds, respectively. Controlling their activities is vital for understanding pathological processes in, and developing therapeutics for glycan-related diseases. Recently, new targeted protein degradation (TPD) technologies, which disable disease-related proteins by degradation, have opened possibilities for proteins that are otherwise hard to inhibit. While TPD within the cytoplasm, cell membrane, and extracellular space can be achieved with current approaches, proteins in the Golgi apparatus can not be degraded by means of the current methods, yet it is a major cellular compartment where most CPEs reside. New TPD strategies targeting Golgi apparatus-resident proteins would be a major solution for CPE-related diseases with unmet medical needs. SWEET DEGRADATION aims to develop strategies that allow for the first time the degradation of proteins located in the Golgi apparatus, opening ways for a new therapeutic modality.
The driving idea behind this proposal is that a molecule can be designed thatselect CPEs in the Golgi for targeted protein degradation. Such molecules, which I term GolgiTACs, will link a CPE to a Golgi transporter, either sortilin or cation-independent mannose-6-phosphate receptor (CI-M6PR), and shuttle CPEs to the lysosome for degradation. In aim 1, I will focus on developing the GolgiTAC technology whereas in aim 2, GolgiTACs will be exploited for targeted protein degradation of CPEs in disease models. In all, SWEET DEGRADATION will deliver a conceptually new general strategy to target Golgi proteins for degradation, thus providing new inroads to develop therapeutics for currently untreatable diseases.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences biochemistry biomolecules carbohydrates
- natural sciences biological sciences biochemistry biomolecules proteins enzymes
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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.1 - European Research Council (ERC)
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(opens in new window) ERC-2024-STG
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2311 EZ Leiden
Netherlands
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