The current state of backbone cyclic peptidomimetics and their application to drug discovery

Samuel J.S. Rubin, Nir Qvit

Research output: Chapter in Book/Report/Conference proceedingChapterpeer-review


Targeting protein–protein interactions for modulation of key disease targets requires a fine balance between selectivity for large interaction surfaces, stability and cell permeability. Traditional small molecule therapeutics are frequently limited by their toxicity due to either unintended interactions (e.g., low selectivity) or production of toxic metabolites and are also not well-suited for targeting PPIs since the corresponding interacting surfaces are relatively large and flat without pockets suitable to bind small molecules with high affinity. On the other hand, protein and antibody therapeutics have been limited by poor cell permeability as well as complex and expensive production. Peptides and especially peptidomimetics (modified peptides, such as cyclic peptides) can be used to overcome many of these limitations and hold great promise for pharmaceutical research and development, with successful drugs already approved. Peptides can be identified from naturally occurring molecules, library screening, and/or rational design. Cyclization can be used to overcome selectivity and stability challenges and enhance pharmacokinetic and pharmacodynamic properties. Several approaches to cyclization have been developed, including backbone cyclization, which we focus on in this chapter. Backbone cyclization preserves side chains that are often critical for biological functionality in a feasible solid-phase peptide synthesis approach via reaction with peptide backbone atoms. Diversity of backbone building blocks and bridge chemistries combined with the cycloscan focused library screening technique allows identification of potent, selective, stable, and cell-permeable cyclic peptidomimetic molecules. Herein, we review and critique applications of backbone cyclic peptidomimetics to neuropeptide, peptide hormone, and protein mimetic drug discovery.

Original languageEnglish
Title of host publicationPeptide and Peptidomimetic Therapeutics
Subtitle of host publicationFrom Bench to Bedside
Number of pages37
ISBN (Electronic)9780128201411
ISBN (Print)9780128204474
StatePublished - 1 Jan 2022

Bibliographical note

Publisher Copyright:
© 2022 Elsevier Inc. All rights reserved.


  • Backbone cyclization
  • cyclization
  • peptides
  • peptidomimetics
  • therapeutic


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