Proteolysis-targeting chimeras in biotherapeutics: Current trends and future applications

The success of inhibitor-based therapeutics is largely constrained by the acquisition of therapeutic resistance, which is partially driven by the undruggable proteome. The emergence of proteolysis targeting chimera (PRO-TAC) technology, designed for degrading proteins involved in specific biological processes, might provide a novel framework for solving the above constraint. A heterobifunctional PROTAC molecule could structurally connect an E3 ubiquitin ligase ligand with a protein of interest (POI)-binding ligand by chemical linkers. Such technology would result in the degradation of the targeted protein via the ubiquitin-proteasome system (UPS), opening up a novel way of selectively inhibiting undruggable proteins. Herein, we will highlight the advantages of PROTAC technology and summarize the current understanding of the potential mechanisms involved in biotherapeutics, with a particular focus on its application and development where therapeutic benefits over classical small -molecule inhibitors have been achieved. Finally, we discuss how this technology can contribute to developing biotherapeutic drugs, such as antivirals against infectious diseases, for use in clinical practices.