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Intracellularly expressed antibodies linked to the E3 ubiquitin ligase domain of STIP1 homology and U-box containing protein 1
(STUB1; CHIP) to enable targeted protein degradation

In vitro and cell culture studies suggest intracellular expression of antibodies linked to the E3 ubiquitin ligase domain of CHIP could promote ubiquitin-mediated degradation of target proteins. In vitro, an E3 ubiquitin ligase domain-linked single-chain variable fragment (scFv) specific for a model target protein caused ubiquitination of the protein. In cultured mammalian cells, plasmid-based expression of an E3 ubiquitin ligase domain-linked antibody-like protein led to degradation of a plasmid-expressed protein from Escherichia coli. Next steps include developing extracellular or transgenic delivery methods and testing the effect of the molecules, called ubiquibodies, on disease-associated proteins in cell culture.
GlaxoSmithKline plc and Arvinas Inc. each have discovery stage programs to find small molecules that promote ubiquitin-mediated protein degradation (see Degradation from within, page 10).

SciBX 7(7); doi:10.1038/scibx.2014.211
Published online Feb. 20, 2014

Patent pending; being licensed to Ubiquizyme Inc.

Protnoff, A.D. et al. J. Biol. Chem.; published online Jan. 28, 2014;
Contact: Matthew P. DeLisa, Cornell University, Ithaca, N.Y.