Macrocyclic peptides as a new class of targeted protein degraders.

Abstract

Targeted protein degraders, in the form of proteolysis targeting chimaeras (PROTACs) and molecular glues, leverage the ubiquitin-proteasome system to catalytically degrade specific target proteins of interest. Because such molecules can be extremely potent, they have attracted considerable attention as a therapeutic modality in recent years. However, while targeted degraders have great potential, they are likely to face many of the same challenges as more traditional small molecules when it comes to their development as therapeutics. In particular, existing targeted degrader design is largely only applicable to the same set of protein targets as traditional small molecules (i.e., ∼15% of the human proteome). Here, we consider the potential of macrocyclic peptides to overcome this limitation. Such molecules possess several features that make them well-suited for the role, including the ability to induce the formation of ternary protein complexes that can involve relatively flat surfaces and their structural commonality with E3 ligase-recruiting peptide degrons. For these reasons, macrocyclic peptides provide the opportunity both to broaden the number of targets accessible to degrader activity and to broaden the number of E3 ligases that can be harnessed to mediate that activity.