Peptide-based PROTACs: Current Challenges and Future Perspectives


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Abstract

Proteolysis-targeting chimeras (PROTACs) are an attractive means to target previously undruggable or drug-resistant mutant proteins. While small molecule-based PROTACs are stable and can cross cell membranes, there is limited availability of suitable small molecule warheads capable of recruiting proteins to an E3 ubiquitin ligase for degradation. With advances in structural biology and in silico protein structure prediction, it is now becoming easier to define highly selective peptides suitable for PROTAC design. As a result, peptide-based PROTACs are becoming a feasible proposition for targeting previously "undruggable" proteins not amenable to small molecule inhibition. In this review, we summarize recent progress in the design and application of peptide-based PROTACs as well as several practical approaches for obtaining candidate peptides for PROTACs. We also discuss the major hurdles preventing the translation of peptide-based PROTACs from bench to bedside, such as their delivery and bioavailability, with the aim of stimulating discussion about how best to accelerate the clinical development of peptide- based PROTACs in the near future.

About the authors

Huidan Wang

School of Life Sciences and Medicine, Shandong University of Technology

Email: info@benthamscience.net

Miao Chen

School of Life Sciences and Medicine, Shandong University of Technology

Email: info@benthamscience.net

Xiaoyuan Zhang

School of Life Sciences and Medicine, Shandong University of Technology

Email: info@benthamscience.net

Songbo Xie

School of Life Sciences and Medicine, Shandong University of Technology

Email: info@benthamscience.net

Jie Qin

School of Life Sciences and Medicine, Shandong University of Technology

Author for correspondence.
Email: info@benthamscience.net

Jingrui Li

School of Life Sciences and Medicine, Shandong University of Technology

Author for correspondence.
Email: info@benthamscience.net

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