Special Chemical Biology Seminar

Multifunctional molecules have redefined how both small molecules, such as catalysts, and large biomolecules, such as cellular enzymes and receptors, can be exploited for gain-of-function processes. In the former, examples of iodoarene and hydrogen bond donor catalysts highlight how multiple functionalities can act cooperatively for asymmetric fluorination reactions and the generation of reactive cationic intermediates from stable precursors.

In the latter, targeted protein degradation has emerged as a powerful strategy to address the canonically difficult-to-drug proteome enabled by multifunctional molecules. However, current technologies are limited to targets with cytosolically-accessible and ligandable domains. As the primary molecular interactors with other cells, secreted and plasma membrane proteins play direct roles in oncogenesis, immune modulation, and aging-related diseases. I will discuss how the development of conjugates capable of binding both a cell surface lysosome targeting receptor and the extracellular domain of a target protein enables degradation of secreted and transmembrane proteins from the cell surface. These lysosome targeting chimeras (LYTACs) consist of a target-binding moiety (e.g. small molecules, antibodies) fused to agonist ligands for the cation-independent mannose-6-phosphate receptor (CI-M6PR), and degrade disease-relevant proteins such as apolipoprotein E4, EGFR, and PD-L1. Mechanistic analysis of LYTAC selectivity using functional genomics revealed new cellular machinery responsible for CI-M6PR recycling, and analysis of selectivity using quantitative proteomics enabled target interactome analysis. Further in vivo work suggests unique opportunities for targeted protein degradation approaches using LYTACs. The strategy outlined here provides a blueprint for expansion of a variety of tailored multifunctional molecules to allow for selective extracellular and transmembrane protein trafficking to lysosomes.