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 is a revolutionary idea by which a heterobifunctional chimera, with the capacity of creating an interaction between a protein of interest (POI) and a degradation system (E3 ubiquitin ligase, autophagy receptors, etc) will induce a process of events in the POI leading to its degradation in a sort of chemical knockdown.
With this programmed protein degradation, toxic and disease-causing proteins can be depleted from cells with potentially effective low TPD doses. These principles have boosted the TPD strategy as a new, attractive paradigm for the development of therapies for the treatment of multiple diseases. Since the initial protacs (Proteolysis targeting chimeras) were reported in the 2000s, the TPD field has expanded extraordinarily, developing innovative chemistry and exploiting multiple degradation approaches. Some of the common strategies for the development of TPD chimeras are shown in the Figure below.
Our group, in collaboration with the “Regulation of the Proteasome” group at the Institut de Biologia Molecular de Barcelona (IBMB), is interested in the use of TPD chimeras for the development of new antiviral and antibacterial agents, as well as antineoplasic agents from the selective degradation of specific kinases and other key factors related to sphingolipid metabolism and cell homeostasis.
Conceptual representation of some of the possible TPD chimeras. For a full account of this topic, see Coll-Martínez, B.; Delgado, A.; Crosas, B. The Potential of Proteolytic Chimeras as Pharmacological Tools and Therapeutic Agents. Molecules 2020, 25 (24), 5956