Cell Penetration of Oxadiazole-containing Macrocycles

Overview

Journal RSC Chem Biol

Publisher Royal Society of Chemistry

Specialty Biology

Date 2024 Apr 5

PMID 38576720

Authors

Sungjoon Huh

Nefeli Batistatou

Jing Wang

George J Saunders

Joshua A Kritzer

Andrei K Yudin

Affiliations

Soon will be listed here.

Abstract

Passive membrane permeability is an important property in drug discovery and biological probe design. To elucidate the cell-penetrating ability of oxadiazole-containing (Odz) peptides, we employed the Chloroalkane Penetration Assay. The present study demonstrates that Odz cyclic peptides can be highly cell-penetrant depending on the position of specific side chains and the chloroalkane tag. Solution NMR shows that Odz cyclic peptides adopt a β-turn conformation. However, despite observing high cell penetration, we observed low passive permeability in experiments with artificial membranes. These findings highlight the complexity of controlling cell penetration for conformationally sensitive macrocycles and suggest that Odz cyclic peptides may provide a framework for designing cell-penetrant cyclic peptides.

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References

Appavoo S, Kaji T, Frost J, Scully C, Yudin A . Development of Endocyclic Control Elements for Peptide Macrocycles. J Am Chem Soc. 2018; 140(28):8763-8770. DOI: 10.1021/jacs.8b04412. View

Hewitt W, Leung S, Pye C, Ponkey A, Bednarek M, Jacobson M . Cell-permeable cyclic peptides from synthetic libraries inspired by natural products. J Am Chem Soc. 2014; 137(2):715-21. DOI: 10.1021/ja508766b. View

Galinis-Luciani D, Nguyen L, Yazdanian M . Is PAMPA a useful tool for discovery?. J Pharm Sci. 2007; 96(11):2886-92. DOI: 10.1002/jps.21071. 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

Tsomaia N . Peptide therapeutics: targeting the undruggable space. Eur J Med Chem. 2015; 94:459-70. DOI: 10.1016/j.ejmech.2015.01.014. View

Lipinski C . Drug-like properties and the causes of poor solubility and poor permeability. J Pharmacol Toxicol Methods. 2001; 44(1):235-49. DOI: 10.1016/s1056-8719(00)00107-6. View

Wender P, Mitchell D, Pattabiraman K, Pelkey E, Steinman L, Rothbard J . The design, synthesis, and evaluation of molecules that enable or enhance cellular uptake: peptoid molecular transporters. Proc Natl Acad Sci U S A. 2000; 97(24):13003-8. PMC: 27168. DOI: 10.1073/pnas.97.24.13003. View

Brown H, Chung M, Uffing A, Batistatou N, Tsang T, Doskocil S . Structure-Based Design of Stapled Peptides That Bind GABARAP and Inhibit Autophagy. J Am Chem Soc. 2022; 144(32):14687-14697. PMC: 9425296. DOI: 10.1021/jacs.2c04699. View

Wang S, Konig G, Roth H, Fouche M, Rodde S, Riniker S . Effect of Flexibility, Lipophilicity, and the Location of Polar Residues on the Passive Membrane Permeability of a Series of Cyclic Decapeptides. J Med Chem. 2021; 64(17):12761-12773. DOI: 10.1021/acs.jmedchem.1c00775. View

10.

Begnini F, Poongavanam V, Atilaw Y, Erdelyi M, Schiesser S, Kihlberg J . Cell Permeability of Isomeric Macrocycles: Predictions and NMR Studies. ACS Med Chem Lett. 2021; 12(6):983-990. PMC: 8201747. DOI: 10.1021/acsmedchemlett.1c00126. View

11.

Bennion B, Be N, McNerney M, Lao V, Carlson E, Valdez C . Predicting a Drug's Membrane Permeability: A Computational Model Validated With in Vitro Permeability Assay Data. J Phys Chem B. 2017; 121(20):5228-5237. DOI: 10.1021/acs.jpcb.7b02914. View

12.

Wang C, Northfield S, Colless B, Chaousis S, Hamernig I, Lohman R . Rational design and synthesis of an orally bioavailable peptide guided by NMR amide temperature coefficients. Proc Natl Acad Sci U S A. 2014; 111(49):17504-9. PMC: 4267368. DOI: 10.1073/pnas.1417611111. View

13.

Saunders G, Yudin A . Property-Driven Development of Passively Permeable Macrocyclic Scaffolds Using Heterocycles. Angew Chem Int Ed Engl. 2022; 61(33):e202206866. DOI: 10.1002/anie.202206866. View

14.

Frost J, Scully C, Yudin A . Oxadiazole grafts in peptide macrocycles. Nat Chem. 2016; 8(12):1105-1111. DOI: 10.1038/nchem.2636. View

15.

Partridge A, Kaan H, Juang Y, Sadruddin A, Lim S, Brown C . Incorporation of Putative Helix-Breaking Amino Acids in the Design of Novel Stapled Peptides: Exploring Biophysical and Cellular Permeability Properties. Molecules. 2019; 24(12). PMC: 6632053. DOI: 10.3390/molecules24122292. View

16.

Peraro L, Deprey K, Moser M, Zou Z, Ball H, Levine B . Cell Penetration Profiling Using the Chloroalkane Penetration Assay. J Am Chem Soc. 2018; 140(36):11360-11369. PMC: 6205923. DOI: 10.1021/jacs.8b06144. View

17.

White T, Renzelman C, Rand A, Rezai T, McEwen C, Gelev V . On-resin N-methylation of cyclic peptides for discovery of orally bioavailable scaffolds. Nat Chem Biol. 2011; 7(11):810-7. PMC: 3210067. DOI: 10.1038/nchembio.664. View

18.

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

19.

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

20.

Deprey K, Kritzer J . Quantitative measurement of cytosolic penetration using the chloroalkane penetration assay. Methods Enzymol. 2020; 641:277-309. PMC: 7872221. DOI: 10.1016/bs.mie.2020.03.003. View