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Bifunctional Small Molecules That Mediate the Degradation of Extracellular Proteins

preprint
revised on 03.08.2020, 12:54 and posted on 04.08.2020, 10:04 by David Caianiello, Mengwen Zhang, Jason Ray, Jake Swartzel, Emily Branham, Egor Chirkin, Venkata Sabbasani, Angela Gong, David Mcdonald, Viswanathan Muthusamy, David Spiegel

Targeted protein degradation (TPD) has emerged as a promising and exciting therapeutic strategy. The majority of existing TPD technologies rely on the ubiquitin-proteasome system, and are therefore limited to targeting intracellular proteins. To address this limitation, we developed a class of modularly designed, bifunctional synthetic molecules called MoDE-As (Molecular Degraders of Extracellular proteins through the Asialoglycoprotein receptor (ASGPR)), which are capable of mediating the degradation of extracellular proteins. MoDE-A molecules mediate the formation of a ternary complex between a target protein and the ASGPR, which is expressed primarily on hepatocytes. The target protein is then endocytosed and degraded by lysosomal proteases. We demonstrated the modularity of the MoDE-A technology by synthesizing bifunctional molecules that induce the degradation of both antibody and pro-inflammatory cytokine proteins. To our knowledge, these data represent the first experimental evidence that non-proteinogenic, synthetic molecules can be employed for the TPD of extracellular proteins both in vitro and in vivo. We believe that TPD mediated by the MoDE-A technology will have widespread applications for disease treatment.

Funding

2T32GM06754 3-17

5T32GM06754 3-12

T32GM067543

BC120554

History

Email Address of Submitting Author

david.spiegel@yale.edu

Institution

Yale University

Country

United States

ORCID For Submitting Author

0000-0002-1102-8012

Declaration of Conflict of Interest

This work is the subject of two published patents: PCT/US2019/26239 and PCT/US2019/26260. DAS is a founder of and has equity in Kleo Pharmaceuticals, an entity focused on the development of bifunctional molecules. DAS also receives honoraria for consulting for Kleo. Kleo has licensed intellectual property from DAS, which is used in this research.

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