GOLGITACs: Targeted Degradation of Golgi Apparatus residing Carbohydrate Processing Enzymes

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.