New review from the Fairlie Group out now in Chemical Reviews. Orally absorbed cyclic peptides.

Orally Absorbed Cyclic Peptides

Nielsen DS, Shepherd NE, Xu W, Lucke AJ, Stoermer MJ and Fairlie DP.

Chem. Rev., In Press
Publication Date (Web): May 25, 2017

Peptides and proteins are important mediators of biological processes, and modulating protein-target interactions is an attractive way to develop new drugs. Unfortunately proteins and peptides are usually only deliverable intravenously, due to their generally poor absorption, or rapid degradation when take orally.

Due to their high specificity however, increasing efforts are being made to modify peptides to increase their oral absorption and consequently, their utility. One approach used by nature and synthetic chemists alike is to increase the stability of peptidic drug candidates by cyclisation.

In this review we survey 125 cyclic peptides and analyse how cyclisation and other modifications affects the flexibility and other molecular properties such as the rule-of-five (RO5) rubric, more commonly associated with small molecule drugs.


Xray crystal structure of cyclosporine A, Dotted lines indicate internal hydrogen bonds. (Loosli 1985).



Xray crystal structure of cyclic hexaleucine , a small bioavailable cyclic peptide. (Hill 2014)

This work was supported by grants from the National Health and Medical Research Council and the Australian Research Council


Orally absorbed cyclic peptides. Daniel S. Nielsen, Nicholas E. Shepherd, Weijun Xu, Andrew J. Lucke, Martin J. Stoermer,* and David P. Fairlie* Chem. Rev., 2017, Article ASAP. Copyright (2017) American Chemical Society. DOI: 10.1021/acs.chemrev.6b00838. TOC graphic reprinted with permission.

The conformation of cyclosporin a in the crystal and in solution.Loosli, H.-R.; Kessler, H.; Oschkinat, H.; Weber, H.-P.; Petcher, T.J.; Widmer, A. Peptide conformations. Part 31†. Helv. Chim. Acta 1985, 68, 682-704. DOI: 10.1002/hlca.19850680319

Cyclic Penta- and Hexa- Leucine Peptides Without N-Methylation Are Orally Absorbed. Timothy A Hill , Rink-Jan J Lohman , Huy Ngoc Hoang , Daniel S Nielsen , Conor CG Scully, Woan Mei Kok , Ligong Liu , Andrew J Lucke , Martin J Stoermer , Christina I Schroeder , Stephanie Chaousis , Barbara Colless , Paul Vincent Bernhardt , David J. Edmonds , David A. Griffith , Charles J. Rotter , Roger B. Ruggeri , David A. Price , Spiros Liras , David J Craik , and David P. Fairlie, ACS Med. Chem. Lett., 2014, 5, 1148-1151. Copyright (2014) American Chemical Society. DOI: 10.1021/ml5002823. TOC graphic reprinted with permission.


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