Modulation of Oral Bioavailability and Metabolism for Closely Related Cyclic Hexapeptides

Overview

Journal Int J Pept Res Ther

Publisher Springer

Date 2018 Mar 13

PMID 29527142

Citations 3

Authors

Thomas Vorherr

Ian Lewis

Joerg Berghausen

Sandrine Desrayaud

Michael Schaefer

Affiliations

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Abstract

Abstract: Recently, a variety of studies concerned with the permeability and oral bioavailability of cyclic peptides have been reported. In particular, strategies aiming at modifying peptides to maintain or to enhance solubility while enabling permeability constitute a significant challenge, but are of high interest to ensure a smooth drug discovery process. Current methodologies include -methylation, matching of hydrogen bonding acceptors and donors across the macrocycle, and additional masking of polarity. In this study, we investigate further the pivotal effects of shielding on permeability and studied the metabolism of the corresponding peptides in more detail by comparing peptide concentrations in the portal versus the jugular vein in rats. Interestingly, minor changes in one particular side chain impacts both permeability and liver metabolism.

Graphical Abstract:

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References

Marzinzik A, Vorherr T . Towards intracellular delivery of peptides. Chimia (Aarau). 2014; 67(12-13):899-904. DOI: 10.2533/chimia.2013.899. View

Kwon Y, Kodadek T . Quantitative comparison of the relative cell permeability of cyclic and linear peptides. Chem Biol. 2007; 14(6):671-7. DOI: 10.1016/j.chembiol.2007.05.006. View

Whitty A, Zhong M, Viarengo L, Beglov D, Hall D, Vajda S . Quantifying the chameleonic properties of macrocycles and other high-molecular-weight drugs. Drug Discov Today. 2016; 21(5):712-7. PMC: 5821503. DOI: 10.1016/j.drudis.2016.02.005. View

Rauf S, Arvidsson P, Albericio F, Govender T, Maguire G, Kruger H . The effect of N-methylation of amino acids (Ac-X-OMe) on solubility and conformation: a DFT study. Org Biomol Chem. 2015; 13(39):9993-10006. DOI: 10.1039/c5ob01565k. View

Schwochert J, Lao Y, Pye C, Naylor M, Desai P, Gonzalez Valcarcel I . Stereochemistry Balances Cell Permeability and Solubility in the Naturally Derived Phepropeptin Cyclic Peptides. ACS Med Chem Lett. 2016; 7(8):757-61. PMC: 4983725. DOI: 10.1021/acsmedchemlett.6b00100. View

Fouche M, Schafer M, Berghausen J, Desrayaud S, Blatter M, Piechon P . Design and Development of a Cyclic Decapeptide Scaffold with Suitable Properties for Bioavailability and Oral Exposure. ChemMedChem. 2016; 11(10):1048-59. DOI: 10.1002/cmdc.201600082. View

Rand A, Leung S, Eng H, Rotter C, Sharma R, Kalgutkar A . Optimizing PK properties of cyclic peptides: the effect of side chain substitutions on permeability and clearance(). Medchemcomm. 2012; 3(10):1282-1289. PMC: 3488302. DOI: 10.1039/C2MD20203D. View

Kiran Marelli U, Bezencon J, Puig E, Ernst B, Kessler H . Enantiomeric cyclic peptides with different Caco-2 permeability suggest carrier-mediated transport. Chemistry. 2015; 21(22):8023-7. DOI: 10.1002/chem.201501270. View

Thansandote P, Harris R, Dexter H, Simpson G, Pal S, Upton R . Improving the passive permeability of macrocyclic peptides: Balancing permeability with other physicochemical properties. Bioorg Med Chem. 2014; 23(2):322-7. DOI: 10.1016/j.bmc.2014.11.034. View

10.

Nielsen D, Hoang H, Lohman R, Diness F, Fairlie D . Total synthesis, structure, and oral absorption of a thiazole cyclic peptide, sanguinamide A. Org Lett. 2012; 14(22):5720-3. DOI: 10.1021/ol3027347. View

11.

Zietek T, Rath E, Haller D, Daniel H . Intestinal organoids for assessing nutrient transport, sensing and incretin secretion. Sci Rep. 2015; 5:16831. PMC: 4652176. DOI: 10.1038/srep16831. View

12.

Hill T, Lohman R, Hoang H, Nielsen D, Scully C, Kok W . Cyclic Penta- and Hexaleucine Peptides without N-Methylation Are Orally Absorbed. ACS Med Chem Lett. 2014; 5(10):1148-51. PMC: 4190638. DOI: 10.1021/ml5002823. View

13.

Giordanetto F, Kihlberg J . Macrocyclic drugs and clinical candidates: what can medicinal chemists learn from their properties?. J Med Chem. 2013; 57(2):278-95. DOI: 10.1021/jm400887j. View

14.

Beck J, Chatterjee J, Laufer B, Kiran M, Frank A, Neubauer S . Intestinal permeability of cyclic peptides: common key backbone motifs identified. J Am Chem Soc. 2012; 134(29):12125-33. DOI: 10.1021/ja303200d. View

15.

Kramer S, Aschmann H, Hatibovic M, Hermann K, Neuhaus C, Brunner C . When barriers ignore the "rule-of-five". Adv Drug Deliv Rev. 2016; 101:62-74. DOI: 10.1016/j.addr.2016.02.001. View

16.

Villar E, Beglov D, Chennamadhavuni S, Porco Jr J, Kozakov D, Vajda S . How proteins bind macrocycles. Nat Chem Biol. 2014; 10(9):723-31. PMC: 4417626. DOI: 10.1038/nchembio.1584. View

17.

Over B, McCarren P, Artursson P, Foley M, Giordanetto F, Gronberg G . Impact of stereospecific intramolecular hydrogen bonding on cell permeability and physicochemical properties. J Med Chem. 2014; 57(6):2746-54. PMC: 3968888. DOI: 10.1021/jm500059t. View

18.

Fouche M, Schafer M, Blatter M, Berghausen J, Desrayaud S, Roth H . Pharmacokinetic Studies around the Mono- and Difunctionalization of a Bioavailable Cyclic Decapeptide Scaffold. ChemMedChem. 2016; 11(10):1060-8. DOI: 10.1002/cmdc.201600083. View

19.

Vorherr T . Modifying peptides to enhance permeability. Future Med Chem. 2015; 7(8):1009-21. DOI: 10.4155/fmc.15.43. View

20.

Veber D, Johnson S, Cheng H, Smith B, Ward K, Kopple K . Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem. 2002; 45(12):2615-23. DOI: 10.1021/jm020017n. View