Targeted protein degradation as a new paradigm in drug discovery. Is there a role for peptides?

Despite the large number of new, therapeutically relevant proteins discovered in recent years, classical drug discovery strategies have not been particularly successful in finding suitable small-molecule modulators.

Targeted protein degradation has raised considerable interest from pharmaceutical/biotech companies and academic groups as a novel paradigm in drug discovery. Two main strategies to generate protein degraders have been identified: 1) Protein-targeting chimeric molecules (PROTACs), and 2) Hydrophobic tagging (HyT). In the first case, multifunctional hybrid molecules containing a ligand of the protein to be degraded and a ligase-recruiting moiety, both joined by a suitable linker, are designed. These chimeric compounds promote ubiquitination of the target protein and its further degradation by the proteasome. In the second strategy, a compound that specifically recognizes the target protein is linked to a bulky hydrophobic ligand (ubiquitin-like), by itself able to trigger the proteasomal degradation machinery. In this highlight I will comment on representative examples of peptide-derived PROTACs that highlight targeted protein degradation as an alternative to classical drug discovery approaches. A substantial contribution from peptide-based PROTACs and peptide-HyT (still unexplored) to the field of induced protein degradation can be envisaged.

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Contributed by Rosario González-Muñiz

Rosario is a Senior Researcher at the Medicinal Chemistry Institute (IQM-CSIC), Madrid. She is involved in peptides, secondary structure mimics and small-molecule peptidomimetics of application in biological/medicinal chemistry programs, especially related to the modulation of ion channels and associated proteins.

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