Backbone Modifications for Increased Stability

Backbone modifications are a key strategy in peptide design, aimed at enhancing the stability of peptides in biological systems. By altering the peptide backbone, researchers can reduce proteolytic degradation, improve bioavailability, and extend the half-life of peptide therapeutics.

Types of Backbone Modifications

Several modifications to the peptide backbone are commonly employed to enhance stability:

• Peptoid Backbone: Peptoids, or N-substituted glycines, differ from peptides by having side chains attached to the nitrogen atom rather than the alpha carbon. This alteration increases resistance to proteases while maintaining biological activity.¹

• Beta-Peptides: These peptides feature an extra methylene group in the backbone, providing enhanced stability against proteolytic enzymes. Beta-peptides are highly resistant to degradation and have been studied for various therapeutic applications.²

• Peptide Cyclization: Cyclization, either through disulfide bridges or head-to-tail cyclization, introduces structural rigidity that reduces susceptibility to proteolytic cleavage. Cyclic peptides often show increased stability and binding affinity for their targets.³

Applications in Therapeutics

Backbone-modified peptides are used in the development of therapeutic peptides with improved pharmacokinetic properties. For instance, cyclic peptides have been employed in cancer therapies and as antimicrobial agents due to their enhanced stability and specificity. Backbone modifications also allow for the incorporation of non-natural amino acids, further increasing peptide resistance to enzymatic degradation.⁴

Conclusion

Backbone modifications offer a powerful approach to improving peptide stability. By introducing peptoid backbones, beta-peptides, or cyclic structures, researchers can design peptides with enhanced resistance to degradation, making them more suitable for therapeutic applications.

Citations and Links

1. Zuckermann, Ronald N. “Peptoid Oligomers as Foldamer Mimics.” ACS Chemical Biology, vol. 8, no. 8, 2013, pp. 1881–1893. doi:10.1021/cb400371e.

2. Seebach, Dieter, and Markus Overhand. “Beta-Peptides: A Surprise at Every Turn.” Biopolymers, vol. 40, no. 3, 1997, pp. 297–299. doi:10.1002/bip.10705.

3. Tyndall, Joel D.A., et al. “Cyclotides: A Natural Backbone-Cyclized Peptide Scaffold.” Drug Discovery Today, vol. 10, no. 7, 2005, pp. 479–485. doi:10.1016/S1359-6446(05)03387-5.

4. Fairlie, David P., et al. “Peptide-Based Drug Design: Discovery and Development.” Medicinal Research Reviews, vol. 29, no. 5, 2009, pp. 670–699. doi:10.1002/med.20149.