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.

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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.

DEKSAN

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

 

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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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New Paper: Drugs and drug-like molecules can modulate the function of mucosal-associated invariant T cells.

Drugs and drug-like molecules can modulate the function of mucosal-associated invariant T cells.
Keller AN, Eckle SB, Xu W, Liu L, Hughes VA, Mak JY, Meehan BS, Pediongco T, Birkinshaw RW, Chen Z, Wang H, D’Souza C, Kjer-Nielsen L, Gherardin NA, Godfrey DI, Kostenko L, Corbett AJ, Purcell AW, Fairlie DP*, McCluskey J*, Rossjohn J*.
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Nature Immunology 2017, 18, 402-411.

The major-histocompatibility-complex-(MHC)-class-I-related molecule MR1 can present activating and non-activating vitamin-B-based ligands to mucosal-associated invariant T cells (MAIT cells). Whether MR1 binds other ligands is unknown. Here we identified a range of small organic molecules, drugs, drug metabolites and drug-like molecules, including salicylates and diclofenac, as MR1-binding ligands. Some of these ligands inhibited MAIT cells ex vivo and in vivo, while others, including diclofenac metabolites, were agonists. Crystal structures of a T cell antigen receptor (TCR) from a MAIT cell in complex with MR1 bound to the non-stimulatory and stimulatory compounds showed distinct ligand orientations and contacts within MR1, which highlighted the versatility of the MR1 binding pocket. The findings demonstrated that MR1 was able to capture chemically diverse structures, spanning mono- and bicyclic compounds, that either inhibited or activated MAIT cells. This indicated that drugs and drug-like molecules can modulate MAIT cell function in mammals.

 

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