Abstract
The induction of protein degradation in a highly selective and efficient way by means of druggable molecules is known as targeted protein degradation (TPD). TPD emerged in the literature as a revolutionary idea: a heterobifunctional chimera with the capacity of creating an interaction between a protein of interest (POI) and a E3 ubiquitin ligase will induce a process of events in the POI, including ubiquitination, targeting to the proteasome, proteolysis and functional silencing, acting as a sort of degradative knockdown. With this programmed protein degradation, toxic and disease-causing proteins could be depleted from cells with potentially effective low drug doses. The proof-of-principle validation of this hypothesis in many studies has made the TPD strategy become a new attractive paradigm for the development of therapies for the treatment of multiple unmet diseases. Indeed, since the initial protacs (Proteolysis targeting chimeras) were posited in the 2000s, the TPD field has expanded extraordinarily, developing innovative chemistry and exploiting multiple degradation approaches. In this article, we review the breakthroughs and recent novel concepts in this highly active discipline.
Highlights
Regulated protein degradation is performed mainly by the ubiquitin-proteasome system, the endocytic and the autophagy pathways, proteasomes and the lysosome being the two main proteolytic hubs in the cell
This “event-driven” mechanism had a precedent in a series of selective estrogen receptor down-regulators (SERDs), a subclass of antiestrogens characterized by inhibiting estrogen binding to its receptor and by inducing a proteasome-dependent receptor degradation
Bioprotacs engineered fusion proteinswhich, that consist of a target binding and an E3 generated anare optimized version of cetuximab, functionalized as a Lysosome-Targeting Chimeras (Lytacs), wasdomain able to catalyze the depletion of EGF receptor (EGFR), offering notable advantages with respect to cetuximab per se
Summary
Regulated protein degradation is performed mainly by the ubiquitin-proteasome system, the endocytic and the autophagy pathways, proteasomes and the lysosome being the two main proteolytic hubs in the cell. These highly complex systems account for the degradation and turnover of most of the proteins in the cell. Different polyubiquitin types are produced by the modification of up to seven internal lysines in the ubiquitin sequence: K6, K11, K27, K29, K33, K48 and K63. Each type of polyubiquitin chain is recognized by a different set of receptors, targeting sequence [5,6]. Each type of polyubiquitin chain is recognized by a different set of receptors, polyubiquitinated cargos to distinct [7]. fates [7]
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