Constrained peptides are an emerging class of pharmaceutical products that are specifically designed to combine the advantageous features of the more traditional therapeutic classes such as, antibodies  which are highly selective structures with low toxicity profiles and small molecules that have the ability to cross cell membranes. This enables them to achieve a greater target specificity. As they are smaller than antibodies, they have a greater bioavailability when administered orally thus, reducing the need for the typically more invasive administration types associated with antibody-based therapies i.e. intravenous administration.

They can assume different structures (as seen in Figure 1) without compromising stability. This establishes another level of specificity and a broader functionality.

  • Basic constrained peptide (Macrocyclic peptide) – as per its name it represents the basic features of a constrained peptide that include high selectivity, durability and permeability. Apart from the common amino acid side chain interactions, use of transition metals in addition to a catalyst can be used to manufacture these structures.
  • Stapled peptide – fixed in its biologically active form with synthetic amino acids to stabilize the a-helical peptide chain, giving the structure greater resistance to proteolytic effects within the cell (Ali et al 2019).
  • Bicyclic peptide – greater metabolic stability than basic and stapled peptides, have additional     applications such as imaging, diagnostics and as enzyme inhibitors. A common method in manufacturing a bicyclic peptide is the formation of disulfide bonds (Rhodes & Pei, 2017).
Figure 1: The different structures that a constrained peptide can undertake (Morrison, 2018).

In 2017, Wiedmann et al successfully designed a constrained peptide inhibitor with a high affinity for the Hepatocyte Nuclear Factor 1β (HNF1β) which is commonly overexpressed in clear cell carcinomas (particularly ovarian cancer). The high selectivity towards a given target coupled with the ability to traverse the cell membrane, opens the possibilityto target cellular mechanisms which were previously off limits to pharmacological intervention. This makes constrained peptides extremely promising.

As constrained peptides are a relatively new concept its unique structures have displayed their high commercial potential evident in recent pre-clinical and clinical studypublications. One notable clinical trial involved Polyphor’s Phase III HER2 negative breast cancer drug – Balixafortide (to be used in combination with Eribulin), which the United States Food and Drug Administration (FDA) has granted a fast track designation. They have recently also been investigated in targeted drug delivery, testing the ability of constrained peptides to increase cancer cell permeability towards traditional anti-cancer drugs. Jerath et al (2020), used constrained peptide to deliver an anti-cancer drug – Methotrexate, in a cell line that had received prior therapy, resulting in a higher cellular uptake in breast and cervical cancer cells compared to “normal” drug administration.

Overall, it’s likely that constrained peptide-based therapeutics will begin to establish themselves in many different indications, due to their vast spectrum of applications within the pharmaceutical industry, it continues to provide researchers with an exciting avenue of therapeutic development to explore.

Written by Hana Haddad, Healthcare Analyst, Oncology.


Ali, A. M., Atmaj, J., Van Oosterwijk, N., Groves, M. R., & Dömling, A. (2019). Stapled Peptides Inhibitors: A New Window for Target Drug Discovery. Computational and structural biotechnology journal17, 263–281.

Jerath, G., Goyal, R., Trivedi, V., Santhoshkumar, T. and Ramakrishnan, V. (2020). Conformationally constrained peptides for drug delivery. Journal of Peptide Science.

Morrison, C. (2018) Constrained peptides’ time to shine? Nature Reviews Drug Discovery,17, pp. 531-533.

Rhodes, C. A., & Pei, D. (2017). Bicyclic Peptides as Next-Generation Therapeutics. Chemistry (Weinheim an der Bergstrasse, Germany)23(52), 12690–12703.

Wiedmann, M., Tan, Y., Wu, Y., Aibara, S., Xu, W., Sore, H., Verma, C., Itzhaki, L., Stewart, M., Brenton, J. and Spring, D. (2017). Development of Cell-Permeable, Non-Helical Constrained Peptides to Target a Key Protein-Protein Interaction in Ovarian Cancer. Angewandte Chemie International Edition, 56(2), pp.524-529.