Chemically Synthetic Strategies for Bicyclic Peptides and Their Application in Drug Development

Shuxian Zhang; Kang Jin

doi:10.7536/PC240613

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Prog Chem ›› 2025, Vol. 37 ›› Issue (5) : 649-669. DOI: 10.7536/PC240613

Review

Chemically Synthetic Strategies for Bicyclic Peptides and Their Application in Drug Development

Shuxian Zhang ,
Kang Jin ^*

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Abstract

In recent decades，along with the improvement of peptide synthetic strategies，the development about bicyclic peptides have been accelerated vigorously，and as a result，more and more bicyclic peptide compounds have entered the clinical trial stage. Through high-throughput screening of peptide compound libraries，the efficiency of obtaining target structures has been greatly increased，further promoting the development of the bicyclic peptide field. Compared with linear and monocyclic peptides，bicyclic peptides have much larger structures and greater structural rigidity，which results in higher affinity and selectivity of the binding to their targets. The absence of terminally free amine and carboxyl groups can also increase the stability of bicyclic peptides against proteolytic enzymes significantly. In addition，the facility of bicyclic peptides to cross cell membranes contributes the improved bioavailability. With the sustainable development and wide application of synthetic technologies，more and more potential bicyclic peptides have been developed successively，laying the foundation for the researches of bicyclic peptide drugs. However，in terms of druggability，there are still many limitations in solubility，conformational stability and in vivo activity，which are urgently need to be solved by means of pharmaceutical preparation and chemically structural modification. This review mainly focuses on the chemical preparation strategies of bicyclic peptides and their applications in drug discovery in recent years.

Contents

1 Introduction

2 Introduction of bicyclic peptides

2.1 Structural characteristics

2.2 Natural bicyclic peptide

3 Synthesis of bicyclic peptides

4 Construction of bicyclic peptide libraries

4.1 Chemical construction of bicyclic peptide libraries

4.2 Biological construction of bicyclic peptide libraries

5 Applications of bicyclic peptides

5.1 Bicyclic peptide coupling（targeted delivery）

5.2 PPIs

5.3 Enzyme inhibitors/agonists

5.4 Receptor Inhibitors

5.5 Antimicrobial bicyclic peptides

5.6 Imaging and contrast

6 Outlook and discussion

Key words

bicyclic peptides / synthetic strategy / bicyclic peptide conjugates / biological activity

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Shuxian Zhang , Kang Jin. Chemically Synthetic Strategies for Bicyclic Peptides and Their Application in Drug Development[J]. Progress in Chemistry. 2025, 37(5): 649-669 https://doi.org/10.7536/PC240613

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Funding

Shandong Provincial Key Research and Development Program（Major Technological Innovation Project）(2021CXGC010501)

National Natural Science Foundation of China(22007059)

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