ACS Publications. Most Trusted. Most Cited. Most Read

OR SEARCH CITATIONS

My Activity
Publications
CONTENT TYPES

Figure 1Loading Img
Download Hi-Res ImageDownload to MS-PowerPointCite This:ACS Med. Chem. Lett. 2016, 7, 8, 757-761
RETURN TO ISSUEPREVLetterNEXT

Stereochemistry Balances Cell Permeability and Solubility in the Naturally Derived Phepropeptin Cyclic Peptides

View Author Information
† Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, California 95064, United States
‡ Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States
*E-mail: [email protected]
Cite this: ACS Med. Chem. Lett. 2016, 7, 8, 757–761
Publication Date (Web):June 6, 2016
https://doi.org/10.1021/acsmedchemlett.6b00100
Copyright © 2016 American Chemical Society
Request reuse permissions

    Article Views

    2195

    Altmetric

    -

    Citations

    49
    LEARN ABOUT THESE METRICS
    Other access options
    Get e-Alerts
    Supporting Info (2)»
    SUBJECTS:

    Abstract

    Abstract Image

    Cyclic peptide (CP) natural products provide useful model systems for mapping “beyond-Rule-of-5” (bRo5) space. We identified the phepropeptins as natural product CPs with potential cell permeability. Synthesis of the phepropeptins and epimeric analogues revealed much more rapid cellular permeability for the natural stereochemical pattern. Despite being more cell permeable, the natural compounds exhibited similar aqueous solubility as the corresponding epimers, a phenomenon explained by solvent-dependent conformational flexibility among the natural compounds. When analyzing the polarity of the solution structures we found that neither the number of hydrogen bonds nor the total polar surface area accurately represents the solvation energies of the high and low dielectric conformations. This work adds to a growing number of natural CPs whose solvent-dependent conformational behavior allows for a balance between aqueous solubility and cell permeability, highlighting structural flexibility as an important consideration in the design of molecules in bRo5 chemical space.

    KEYWORDS:

    Read this article

    To access this article, please review the available access options below.

    Get instant access

    Purchase Access

    Read this article for 48 hours. Check out below using your ACS ID or as a guest.

    Recommended

    Access through Your Institution

    You may have access to this article through your institution.

    Your institution does not have access to this content. You can change your affiliated institution below.

    Supporting Information

    ARTICLE SECTIONS
    Jump To

    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmedchemlett.6b00100.

    • Additional information (PDF)

    • Solution structures (MOL)

    Terms & Conditions

    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

    Cited By

    This article is cited by 49 publications.

    1. Dongjae Lee, Jieun Choi, Min June Yang, Chin-Ju Park, Jiwon Seo. Controlling the Chameleonic Behavior and Membrane Permeability of Cyclosporine Derivatives via Backbone and Side Chain Modifications. Journal of Medicinal Chemistry 2023, 66 (18) , 13189-13204. https://doi.org/10.1021/acs.jmedchem.3c01140
    2. Mai Mizuno-Kaneko, Ichihiko Hashimoto, Kenta Miyahara, Masahiro Kochi, Noriyuki Ohashi, Kyosuke Tsumura, Koo Suzuki, Takashi Tamura. Molecular Design of Cyclic Peptides with Cell Membrane Permeability and Development of MDMX-p53 Inhibitor. ACS Medicinal Chemistry Letters 2023, 14 (9) , 1174-1178. https://doi.org/10.1021/acsmedchemlett.3c00102
    3. Barmak Mostofian, Holli-Joi Martin, Asghar Razavi, Shivam Patel, Bryce Allen, Woody Sherman, Jesus A Izaguirre. Targeted Protein Degradation: Advances, Challenges, and Prospects for Computational Methods. Journal of Chemical Information and Modeling 2023, 63 (17) , 5408-5432. https://doi.org/10.1021/acs.jcim.3c00603
    4. Man-Ling Lee, Sherif Farag, Joselyn S. Del Cid, Charlene Bashore, Kenneth K. Hallenbeck, Alberto Gobbi, Christian N. Cunningham. Identification of Macrocyclic Peptide Families from Combinatorial Libraries Containing Noncanonical Amino Acids Using Cheminformatics and Bioinformatics Inspired Clustering. ACS Chemical Biology 2023, 18 (6) , 1425-1434. https://doi.org/10.1021/acschembio.3c00159
    5. Stephanie M. Linker, Christian Schellhaas, Anna S. Kamenik, Mac M. Veldhuizen, Franz Waibl, Hans-Jörg Roth, Marianne Fouché, Stephane Rodde, Sereina Riniker. Lessons for Oral Bioavailability: How Conformationally Flexible Cyclic Peptides Enter and Cross Lipid Membranes. Journal of Medicinal Chemistry 2023, 66 (4) , 2773-2788. https://doi.org/10.1021/acs.jmedchem.2c01837
    6. Anna A. Rzepiela, Lauren A. Viarengo-Baker, Victor Tatarskii, Roman Kombarov, Adrian Whitty. Conformational Effects on the Passive Membrane Permeability of Synthetic Macrocycles. Journal of Medicinal Chemistry 2022, 65 (15) , 10300-10317. https://doi.org/10.1021/acs.jmedchem.1c02090
    7. Tomi K. Sawyer Kaustav Biswas . Peptide Drug Discovery Raison d’Etre: Engineering Mindset, Design Rules and Screening Tools. , 1-25. https://doi.org/10.1021/bk-2022-1417.ch001
    8. Christina Helmling Christian N. Cunningham . mRNA Display and Its Growing Potential in the Discovery of De Novo Therapeutic Peptide Candidates. , 27-53. https://doi.org/10.1021/bk-2022-1417.ch002
    9. Emel Adaligil Wayne J. Fairbrother . NMR Spectroscopy for Studying Peptide Conformations and Cell Permeability. , 155-177. https://doi.org/10.1021/bk-2022-1417.ch006
    10. Jaru Taechalertpaisarn, Satoshi Ono, Okimasa Okada, Timothy C. Johnstone, R. Scott Lokey. A New Amino Acid for Improving Permeability and Solubility in Macrocyclic Peptides through Side Chain-to-Backbone Hydrogen Bonding. Journal of Medicinal Chemistry 2022, 65 (6) , 5072-5084. https://doi.org/10.1021/acs.jmedchem.2c00010
    11. Victoria G. Klein, Walter M. Bray, Hao-Yuan Wang, Quinn Edmondson, Joshua Schwochert, Satoshi Ono, Matthew R. Naylor, Alexandra C. Turmon, Justin H. Faris, Okimasa Okada, Jack Taunton, R. Scott Lokey. Identifying the Cellular Target of Cordyheptapeptide A and Synthetic Derivatives. ACS Chemical Biology 2021, 16 (8) , 1354-1364. https://doi.org/10.1021/acschembio.1c00094
    12. Dongjae Lee, Sungjin Lee, Jieun Choi, Yoo-Kyung Song, Min Ju Kim, Dae-Seop Shin, Myung Ae Bae, Yong-Chul Kim, Chin-Ju Park, Kyeong-Ryoon Lee, Jun-Ho Choi, Jiwon Seo. Interplay among Conformation, Intramolecular Hydrogen Bonds, and Chameleonicity in the Membrane Permeability and Cyclophilin A Binding of Macrocyclic Peptide Cyclosporin O Derivatives. Journal of Medicinal Chemistry 2021, 64 (12) , 8272-8286. https://doi.org/10.1021/acs.jmedchem.1c00211
    13. Alexander C. Brueckner, Qiaolin Deng, Ann E. Cleves, Charles A. Lesburg, Juan C. Alvarez, Mikhail Y. Reibarkh, Edward C. Sherer, Ajay N. Jain. Conformational Strain of Macrocyclic Peptides in Ligand–Receptor Complexes Based on Advanced Refinement of Bound-State Conformers. Journal of Medicinal Chemistry 2021, 64 (6) , 3282-3298. https://doi.org/10.1021/acs.jmedchem.0c02159
    14. Rasha Jwad, Daniel Weissberger, Luke Hunter. Strategies for Fine-Tuning the Conformations of Cyclic Peptides. Chemical Reviews 2020, 120 (17) , 9743-9789. https://doi.org/10.1021/acs.chemrev.0c00013
    15. Anna S. Kamenik, Johannes Kraml, Florian Hofer, Franz Waibl, Patrick K. Quoika, Ursula Kahler, Michael Schauperl, Klaus R. Liedl. Macrocycle Cell Permeability Measured by Solvation Free Energies in Polar and Apolar Environments. Journal of Chemical Information and Modeling 2020, 60 (7) , 3508-3517. https://doi.org/10.1021/acs.jcim.0c00280
    16. Haigang Song, Ju̅ratè Fahrig-Kamarauskaitè, Emmanuel Matabaro, Hannelore Kaspar, Sally L. Shirran, Christina Zach, Amy Pace, Bozhidar-Adrian Stefanov, James H. Naismith, Markus Künzler. Substrate Plasticity of a Fungal Peptide α-N-Methyltransferase. ACS Chemical Biology 2020, 15 (7) , 1901-1912. https://doi.org/10.1021/acschembio.0c00237
    17. Solomon D. Appavoo, Sungjoon Huh, Diego B. Diaz, Andrei K. Yudin. Conformational Control of Macrocycles by Remote Structural Modification. Chemical Reviews 2019, 119 (17) , 9724-9752. https://doi.org/10.1021/acs.chemrev.8b00742
    18. Satoshi Ono, Matthew R. Naylor, Chad E. Townsend, Chieko Okumura, Okimasa Okada, R. Scott Lokey. Conformation and Permeability: Cyclic Hexapeptide Diastereomers. Journal of Chemical Information and Modeling 2019, 59 (6) , 2952-2963. https://doi.org/10.1021/acs.jcim.9b00217
    19. Laura A. T. Cleghorn, Peter C. Ray, Joshua Odingo, Anuradha Kumar, Heather Wescott, Aaron Korkegian, Thierry Masquelin, Abraham Lopez Moure, Caroline Wilson, Susan Davis, Margaret Huggett, Penelope Turner, Alasdair Smith, Ola Epemolu, Fabio Zuccotto, Jennifer Riley, Paul Scullion, Yoko Shishikura, Liam Ferguson, Joaquin Rullas, Laura Guijarro, Kevin D. Read, Simon R. Green, Phil Hipskind, Tanya Parish, Paul G. Wyatt. Identification of Morpholino Thiophenes as Novel Mycobacterium tuberculosis Inhibitors, Targeting QcrB. Journal of Medicinal Chemistry 2018, 61 (15) , 6592-6608. https://doi.org/10.1021/acs.jmedchem.8b00172
    20. Lissa S. Tsutsumi, John M. Elmore, Uyen T. Dang, Miranda J. Wallace, Ravikanthreddy Marreddy, Robin B. Lee, Ghee T. Tan, Julian G. Hurdle, Richard E. Lee, Dianqing Sun. Solid-Phase Synthesis and Antibacterial Activity of Cyclohexapeptide Wollamide B Analogs. ACS Combinatorial Science 2018, 20 (3) , 172-185. https://doi.org/10.1021/acscombsci.7b00189
    21. Laura K. Buckton and Shelli R. McAlpine . Improving the Cell Permeability of Polar Cyclic Peptides by Replacing Residues with Alkylated Amino Acids, Asparagines, and d-Amino Acids. Organic Letters 2018, 20 (3) , 506-509. https://doi.org/10.1021/acs.orglett.7b03363
    22. Marion L'Exact, Christian Comeau, Alix Bourhis, Olivier Boisvert, Ulrike Fröhlich, Danny Létourneau, Éric Marsault, Pierre Lavigne, Michel Grandbois, Pierre-Luc Boudreault. Beyond Rule-of-five: Permeability Assessment of Semipeptidic Macrocycles. Biochimica et Biophysica Acta (BBA) - Biomembranes 2023, 1865 (7) , 184196. https://doi.org/10.1016/j.bbamem.2023.184196
    23. Sungjoon Huh, George J. Saunders, Andrei K. Yudin. Single Atom Ring Contraction of Peptide Macrocycles Using Cornforth Rearrangement. Angewandte Chemie 2023, 135 (5) https://doi.org/10.1002/ange.202214729
    24. Sungjoon Huh, George J. Saunders, Andrei K. Yudin. Single Atom Ring Contraction of Peptide Macrocycles Using Cornforth Rearrangement. Angewandte Chemie International Edition 2023, 62 (5) https://doi.org/10.1002/anie.202214729
    25. Nadja Blasey, Daria Rehrmann, Anna Katharina Riebisch, Sabrina Mühlen. Targeting bacterial pathogenesis by inhibiting virulence-associated Type III and Type IV secretion systems. Frontiers in Cellular and Infection Microbiology 2023, 12 https://doi.org/10.3389/fcimb.2022.1065561
    26. Maria-Jesus Blanco. New Therapeutic Modalities: Transforming Drug Discovery and Development. 2023, 1-21. https://doi.org/10.1007/978-3-030-73317-9_135-1
    27. Chao Lv, Ying Li, Yuxia Wei, Jiayu Wang, Hui Yu, Feng Gao, Chao Zhu, Xiangdi Jia, Mingqiong Tong, Pingxuan Dong, Qianqian Gao, Longlong Geng. Research Progress on Small Molecular Inhibitors of the Type 3 Secretion System. Molecules 2022, 27 (23) , 8348. https://doi.org/10.3390/molecules27238348
    28. George J. Saunders, Andrei K. Yudin. Property‐Driven Development of Passively Permeable Macrocyclic Scaffolds Using Heterocycles**. Angewandte Chemie 2022, 134 (33) https://doi.org/10.1002/ange.202206866
    29. George J. Saunders, Andrei K. Yudin. Property‐Driven Development of Passively Permeable Macrocyclic Scaffolds Using Heterocycles**. Angewandte Chemie International Edition 2022, 61 (33) https://doi.org/10.1002/anie.202206866
    30. Timothy J. McTiernan, Diego B. Diaz, George J. Saunders, Fiona Sprang, Andrei K. Yudin. Navigating complex peptide structures using macrocycle conformational maps. RSC Chemical Biology 2022, 3 (6) , 739-747. https://doi.org/10.1039/D2CB00016D
    31. Tomi Sawyer. Entrepreneurial Drug Hunter. 2022, 273-292. https://doi.org/10.1002/9781119627784.ch12
    32. Jianguo Li, Srinivasaraghavan Kannan, Pietro Aronica, Christopher J. Brown, Anthony W. Partridge, Chandra S. Verma. Molecular descriptors suggest stapling as a strategy for optimizing membrane permeability of cyclic peptides. The Journal of Chemical Physics 2022, 156 (6) https://doi.org/10.1063/5.0078025
    33. Tomi K. Sawyer. Emerging Peptide Drug Modalities for Intracellular Target Space. 2022, 267-286. https://doi.org/10.1007/978-3-031-04544-8_8
    34. Matthew Holcomb, Diogo Santos-Martins, Andreas F. Tillack, Stefano Forli. Performance evaluation of flexible macrocycle docking in AutoDock. QRB Discovery 2022, 3 https://doi.org/10.1017/qrd.2022.18
    35. Céline Dard, Baptiste Leforestier, Flaviane Francisco Hilário, Mohamed Dit Mady Traoré, Marie-Ange Lespinasse, Basile Pérès, Marie-Carmen Molina, Rossimiriam Pereira de Freitas, Anne Milet, Danièle Maubon, Yung-Sing Wong. Crossing of the Cystic Barriers of Toxoplasma gondii by the Fluorescent Coumarin Tetra-Cyclopeptide. Molecules 2021, 26 (24) , 7506. https://doi.org/10.3390/molecules26247506
    36. Lauren A. Viarengo-Baker, Lauren E. Brown, Anna A. Rzepiela, Adrian Whitty. Defining and navigating macrocycle chemical space. Chemical Science 2021, 12 (12) , 4309-4328. https://doi.org/10.1039/D0SC05788F
    37. Doris Zane, Paul L. Feldman, Tomi Sawyer, Zhanna Sobol, Jessica Hawes. Development and Regulatory Challenges for Peptide Therapeutics. International Journal of Toxicology 2021, 40 (2) , 108-124. https://doi.org/10.1177/1091581820977846
    38. Laura K. Buckton, Marwa N. Rahimi, Shelli R. McAlpine. Cyclic Peptides as Drugs for Intracellular Targets: The Next Frontier in Peptide Therapeutic Development. Chemistry – A European Journal 2021, 27 (5) , 1487-1513. https://doi.org/10.1002/chem.201905385
    39. Rink-Jan Lohman, Daniel S. Nielsen, W. Mei Kok, Huy N. Hoang, Timothy A. Hill, David P. Fairlie. Mirror image pairs of cyclic hexapeptides have different oral bioavailabilities and metabolic stabilities. Chemical Communications 2019, 55 (89) , 13362-13365. https://doi.org/10.1039/C9CC06234C
    40. Jumpei Morimoto, Rei Amano, Takahiro Ono, Shinsuke Sando. A parallel permeability assay of peptides across artificial membranes and cell monolayers using a fluorogenic reaction. Organic & Biomolecular Chemistry 2019, 17 (11) , 2887-2891. https://doi.org/10.1039/C9OB00133F
    41. Maria-Jesus Blanco. Building upon Nature’s Framework: Overview of Key Strategies Toward Increasing Drug-Like Properties of Natural Product Cyclopeptides and Macrocycles. 2019, 203-233. https://doi.org/10.1007/978-1-4939-9504-2_10
    42. Philipp Ermert, Anatol Luther, Peter Zbinden, Daniel Obrecht. Frontier Between Cyclic Peptides and Macrocycles. 2019, 147-202. https://doi.org/10.1007/978-1-4939-9504-2_9
    43. Yuantao Huo, Laura K. Buckton, Jack L. Bennett, Eloise C. Smith, Frances L. Byrne, Kyle L. Hoehn, Marwa N. Rahimi, Shelli R. McAlpine. Delivering bioactive cyclic peptides that target Hsp90 as prodrugs. Journal of Enzyme Inhibition and Medicinal Chemistry 2019, 34 (1) , 728-739. https://doi.org/10.1080/14756366.2019.1580276
    44. Tomi K. Sawyer, Anthony W. Partridge, Hung Yi Kristal Kaan, Yu-Chi Juang, Shuhui Lim, Charles Johannes, Tsz Ying Yuen, Chandra Verma, Srinivasaraghavan Kannan, Pietro Aronica, Yaw Sing Tan, Brad Sherborne, Sookhee Ha, Jerome Hochman, Shiying Chen, Laura Surdi, Andrea Peier, Berengere Sauvagnat, Peter J. Dandliker, Christopher J. Brown, Simon Ng, Fernando Ferrer, David P. Lane. Macrocyclic α helical peptide therapeutic modality: A perspective of learnings and challenges. Bioorganic & Medicinal Chemistry 2018, 26 (10) , 2807-2815. https://doi.org/10.1016/j.bmc.2018.03.008
    45. Leo L. H. Lee, Laura K. Buckton, Shelli R. McAlpine. Converting polar cyclic peptides into membrane permeable molecules using N ‐methylation. Peptide Science 2018, 110 (3) https://doi.org/10.1002/pep2.24063
    46. Thomas Vorherr, Ian Lewis, Joerg Berghausen, Sandrine Desrayaud, Michael Schaefer. Modulation of Oral Bioavailability and Metabolism for Closely Related Cyclic Hexapeptides. International Journal of Peptide Research and Therapeutics 2018, 24 (1) , 35-48. https://doi.org/10.1007/s10989-017-9590-8
    47. Q. Nhu N. Nguyen, Joshua Schwochert, Dean J. Tantillo, R. Scott Lokey. Using 1 H and 13 C NMR chemical shifts to determine cyclic peptide conformations: a combined molecular dynamics and quantum mechanics approach. Physical Chemistry Chemical Physics 2018, 20 (20) , 14003-14012. https://doi.org/10.1039/C8CP01616J
    48. Hanh Lam, Joshua Schwochert, Yongtong Lao, Tannia Lau, Cameron Lloyd, Justin Luu, Olivia Kooner, Jessica Morgan, Scott Lokey, Victoria Auerbuch. Synthetic Cyclic Peptomers as Type III Secretion System Inhibitors. Antimicrobial Agents and Chemotherapy 2017, 61 (9) https://doi.org/10.1128/AAC.00060-17
    49. Matthew R Naylor, Andrew T Bockus, Maria-Jesus Blanco, R Scott Lokey. Cyclic peptide natural products chart the frontier of oral bioavailability in the pursuit of undruggable targets. Current Opinion in Chemical Biology 2017, 38 , 141-147. https://doi.org/10.1016/j.cbpa.2017.04.012
    Download PDF

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    You’ve supercharged your research process with ACS and Mendeley!

    STEP 1:
    Click to create an ACS ID

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    MENDELEY PAIRING EXPIRED
    Your Mendeley pairing has expired. Please reconnect