Banik SM,
Pedram K,
Wisnovsky S,
Riley NM,
Bertozzi CR.
* Stanford University and Howard Hughes Medical Institute, Stanford, USA
Lysosome Targeting Chimeras (LYTACs) for the Degradation of Secreted and Membrane
Proteins.
ChemRxiv 2019;
DOI:
10.26434/chemrxiv.7927061.v1
Key words
lysosome targeting chimeras - LYTACs - protein degradation - lysosome
Significance
Lysosomal degradation makes use of cell-surface lysosomal targeting receptors (LTR),
which facilitate the transport of proteins into the lysosome. The authors developed
so-called LYTACs, which are chimeric molecules that can bind both an extracellular
protein and an LTR, allowing for degradation of non-cytosolic proteins of interest
in the lysosome. LYTACs are complementary to PROTACs (proteolysis targeting chimeras),
which primarily target cytosolic proteins.
Comment
Mannose-6-phosphate receptor M6PR (or IGF2R) recognizes and binds mannose-6-phosphate
residues on proteins and transports them to the lysosome for degradation. The LYTACs
presented herein use glycopolypeptides of varying length, which can be attached to
an antibody for the POI in a modular fashion using click chemistry. The versatile
applicability is demonstrated by successfully targeting different extracellular proteins.
