Taming Conformational Heterogeneity on Ion Racetrack to Unveil Principles that Drive Membrane Permeation of Cyclosporines

Limbach, Miranda N.; Lindberg, Edward T.; Olivos, Hernando J.; van Tetering, Lara; Steren, Carlos A.; Martens, Jonathan; Ngo, Van A.; Oomens, Jos; Do, Thanh D.

doi:10.1021/jacsau.4c00011

Title: Taming Conformational Heterogeneity on Ion Racetrack to Unveil Principles that Drive Membrane Permeation of Cyclosporines

Journal Article · 16 March 2024 · JACS Au

DOI: https://doi.org/10.1021/jacsau.4c00011 · OSTI ID:2324728

^[1]; Lindberg, Edward T. ^[1]; Olivos, Hernando J. ^[2];

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^[3];

^[4]; Oomens, Jos ^[3];

^[1]

University of Tennessee, Knoxville, TN (United States)
Waters Corporation, Milford, MA (United States)
Radboud University, Nijmegen (Netherlands)
Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States). National Center for Computational Sciences (NCCS)

Our study reveals the underlying principles governing the passive membrane permeability in three large N-methylated macrocyclic peptides (N-MeMPs): cyclosporine A (CycA), Alisporivir (ALI), and cyclosporine H (CycH). We determine a series of conformers required for robust passive membrane diffusion and those relevant to other functions, such as binding to protein targets or intermediates, in the presence of solvent additives. We investigate the conformational interconversions and establish correlations with the membrane permeability. Nuclear magnetic resonance (NMR) and cyclic ion-mobility spectrometry-mass spectrometry (cIMS-MS) are employed to characterize conformational heterogeneity and identify cis-amides relevant for good membrane permeability. In addition, ion mobility selected cIMS-MS and infrared (IR) multiple-photon dissociation (IRMPD) spectroscopy experiments are conducted to evaluate the energy barriers between conformations. We observe that CycA and ALI, both cyclosporines with favorable membrane permeabilities, display multiple stable and well-defined conformers. In contrast, CycH, an epimer of CycA with limited permeability, exhibits fewer and fewer stable conformers. We demonstrate the essential role of the conformational shift from the aqueous cis MeVal11–MeBmt1 state (A1) to the closed conformation featuring cis MeLeu9–MeLeu10 (C1) in facilitating membrane permeation. Additionally, we highlight that the transition from A1 to the all-trans open conformation (O1) is specifically triggered by the presence of CaCl₂. We also capture a set of conformers with cis Sar3–MeLeu4, MeLeu9–MeLeu10, denoted as I. Conformationally selected cIMS-MS and IRMPD data of [CycA+Ca]²⁺ show immediate repopulation of the original population distribution, suggesting that CaCl₂ smooths out the energy barriers. Finally, our work presents an improved sampling molecular dynamics approach based on a refined force field that not only consistently and accurately captures established conformers of cyclosporines but also exhibits strong predictive capabilities for novel conformers.

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Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States); Univ. of Tennessee, Knoxville, TN (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); National Science Foundation (NSF); Eli Lily and Company

Grant/Contract Number:: AC05-00OR22725; 2138259; 2138286; 2138307; 2137603; 2138296

OSTI ID:: 2324728

Alternate ID(s):: OSTI ID: 2333760; OSTI ID: 2339796

Journal Information:: JACS Au, Vol. 4, Issue 4; ISSN 2691-3704

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

References (69)

Cyclosporin A: Conformational Complexity and Chameleonicity Ono, Satoshi; Naylor, Matthew R.; Townsend, Chad E. Journal of Chemical Information and Modeling, Vol. 61, Issue 11 https://doi.org/10.1021/acs.jcim.1c00771	journal	October 2021
Dielectric Properties of Aqueous Ionic Solutions. Parts I and II Hasted, J. B.; Ritson, D. M.; Collie, C. H. The Journal of Chemical Physics, Vol. 16, Issue 1 https://doi.org/10.1063/1.1746645	journal	January 1948
The influence of drug-like concepts on decision-making in medicinal chemistry Leeson, Paul D.; Springthorpe, Brian Nature Reviews Drug Discovery, Vol. 6, Issue 11 https://doi.org/10.1038/nrd2445	journal	November 2007
Detection of conformation types of cyclosporin retaining intramolecular hydrogen bonds by mass spectrometry Hyung, Suk-Joon; Feng, Xidong; Che, Ye Analytical and Bioanalytical Chemistry, Vol. 406, Issue 24 https://doi.org/10.1007/s00216-014-8023-1	journal	July 2014
Ion size effects on the dynamic and static dielectric properties of aqueous alkali solutions Wei, Yan-Zhen; Chiang, Ping; Sridhar, S. The Journal of Chemical Physics, Vol. 96, Issue 6 https://doi.org/10.1063/1.462792	journal	March 1992
Controlling the Chameleonic Behavior and Membrane Permeability of Cyclosporine Derivatives via Backbone and Side Chain Modifications Lee, Dongjae; Choi, Jieun; Yang, Min June Journal of Medicinal Chemistry, Vol. 66, Issue 18 https://doi.org/10.1021/acs.jmedchem.3c01140	journal	September 2023
Dielectric Properties of Aqueous NaCl Solutions at Microwave Frequencies Nörtemann, K.; Hilland, J.; Kaatze, U. The Journal of Physical Chemistry A, Vol. 101, Issue 37 https://doi.org/10.1021/jp971623a	journal	September 1997
Thiocyclosporins: Preparation, Solution and Crystal Structure, and Immunosuppressive Activity Seebach, Dieter; Ko, Soo Y.; Kessler, Horst Helvetica Chimica Acta, Vol. 74, Issue 8 https://doi.org/10.1002/hlca.19910740833	journal	December 1991
Novel backbone conformation of cyclosporin A: the complex with lithium chloride Koeck, Matthias; Kessler, Horst; Seebach, Dieter Journal of the American Chemical Society, Vol. 114, Issue 7 https://doi.org/10.1021/ja00033a048	journal	March 1992
Lithium chloride perturbation of cis-trans peptide bond equilibria: effect on conformational equilibria in cyclosporin A and on time-dependent inhibition of cyclophilin Kofron, James L.; Kuzmic, Petr; Kishore, Vimal Journal of the American Chemical Society, Vol. 114, Issue 7 https://doi.org/10.1021/ja00033a047	journal	March 1992
Cyclosporine A: Chemistry and Toxicity – A Review Patocka, Jiri; Nepovimova, Eugenie; Kuca, Kamil Current Medicinal Chemistry, Vol. 27 https://doi.org/10.2174/0929867327666201006153202	journal	October 2020
Beyond cyclosporine A: conformation-dependent passive membrane permeabilities of cyclic peptide natural products Ahlbach, Christopher L.; Lexa, Katrina W.; Bockus, Andrew T. Future Medicinal Chemistry, Vol. 7, Issue 16 https://doi.org/10.4155/fmc.15.78	journal	October 2015
1H and 13C-NMR and Molecular Dynamics Studies of Cyclosporin A Interacting with Magnesium(II) or Cerium(III) in Acetonitrile. Conformational Changes and cis-trans Conversion of Peptide Bonds Bernardi, Francesca; Gaggelli, Elena; Molteni, Elena Biophysical Journal, Vol. 90, Issue 4 https://doi.org/10.1529/biophysj.105.074245	journal	February 2006
The R.E.D. tools: advances in RESP and ESP charge derivation and force field library building Dupradeau, François-Yves; Pigache, Adrien; Zaffran, Thomas Physical Chemistry Chemical Physics, Vol. 12, Issue 28 https://doi.org/10.1039/c0cp00111b	journal	January 2010
Cyclosporin Structure and Permeability: From A to Z and Beyond Corbett, Karen M.; Ford, Leigh; Warren, Dallas B. Journal of Medicinal Chemistry, Vol. 64, Issue 18 https://doi.org/10.1021/acs.jmedchem.1c00580	journal	September 2021
NMR studies of the Na+, Mg2+ and Ca2+ complexes of cyclosporin A Carver, John A.; Rees, Nicholas H.; Turner, David L. Journal of the Chemical Society, Chemical Communications, Issue 22 https://doi.org/10.1039/c39920001682	journal	January 1992
Synthesis and Crystal Structure Determination of Cyclosporin H Jegorov, Alexandr; Cvak, Ladislav; Husek, Aleš Collection of Czechoslovak Chemical Communications, Vol. 65, Issue 8 https://doi.org/10.1135/cccc20001317	journal	January 2000
Conformations of Macrocyclic Peptides Sampled by Nuclear Magnetic Resonance: Models for Cell-Permeability Rüdisser, Simon H.; Matabaro, Emmanuel; Sonderegger, Lukas Journal of the American Chemical Society, Vol. 145, Issue 50 https://doi.org/10.1021/jacs.3c09367	journal	December 2023
Rgg protein structure–function and inhibition by cyclic peptide compounds Parashar, Vijay; Aggarwal, Chaitanya; Federle, Michael J. Proceedings of the National Academy of Sciences, Vol. 112, Issue 16 https://doi.org/10.1073/pnas.1500357112	journal	April 2015
2021 FDA approvals Mullard, Asher Nature Reviews Drug Discovery, Vol. 21, Issue 2 https://doi.org/10.1038/d41573-022-00001-9	journal	January 2022
Interplay among Conformation, Intramolecular Hydrogen Bonds, and Chameleonicity in the Membrane Permeability and Cyclophilin A Binding of Macrocyclic Peptide Cyclosporin O Derivatives Lee, Dongjae; Lee, Sungjin; Choi, Jieun Journal of Medicinal Chemistry, Vol. 64, Issue 12 https://doi.org/10.1021/acs.jmedchem.1c00211	journal	June 2021
NMR structure of cyclosporin A bound to cyclophilin in aqueous solution Weber, C.; Wider, G.; Von Freyberg, B. Biochemistry, Vol. 30, Issue 26 https://doi.org/10.1021/bi00240a029	journal	July 1991
Peptide conformations. Part 31. The conformation of cyclosporin a in the crystal and in solution Loosli, Hans‐Rudolf; Kessler, Horst; Oschkinat, Hartmut Helvetica Chimica Acta, Vol. 68, Issue 3 https://doi.org/10.1002/hlca.19850680319	journal	May 1985
Cyclosporins: Structure−Activity Relationships for the Inhibition of the Human FPR1 Formylpeptide Receptor Loor, Francis; Tiberghien, Françoise; Wenandy, Tom Journal of Medicinal Chemistry, Vol. 45, Issue 21 https://doi.org/10.1021/jm010987v	journal	September 2002
Macrocycles: lessons from the distant past, recent developments, and future directions Yudin, Andrei K. Chemical Science, Vol. 6, Issue 1 https://doi.org/10.1039/C4SC03089C	journal	January 2015
Drugging the 'undruggable' cancer targets Dang, Chi V.; Reddy, E. Premkumar; Shokat, Kevan M. Nature Reviews Cancer, Vol. 17, Issue 8 https://doi.org/10.1038/nrc.2017.36	journal	June 2017
Gas-phase infrared multiple photon dissociation spectroscopy of mass-selected molecular ions Oomens, Jos; Sartakov, Boris G.; Meijer, Gerard International Journal of Mass Spectrometry, Vol. 254, Issue 1-2 https://doi.org/10.1016/j.ijms.2006.05.009	journal	July 2006
Dielectric properties of electrolytic solutions Navarkhele, V. V.; Agrawal, R. S.; Kurtadikar, M. L. Pramana, Vol. 51, Issue 3-4 https://doi.org/10.1007/BF02828943	journal	September 1998
Dielectric Constant of Ionic Solutions: A Field-Theory Approach Levy, Amir; Andelman, David; Orland, Henri Physical Review Letters, Vol. 108, Issue 22 https://doi.org/10.1103/PhysRevLett.108.227801	journal	May 2012
Cyclic Ion Mobility Mass Spectrometry Distinguishes Anomers and Open-Ring Forms of Pentasaccharides Ujma, Jakub; Ropartz, David; Giles, Kevin Journal of The American Society for Mass Spectrometry, Vol. 30, Issue 6 https://doi.org/10.1007/s13361-019-02168-9	journal	April 2019
Interconversion Rates between Conformational States as Rationale for the Membrane Permeability of Cyclosporines Witek, Jagna; Mühlbauer, Max; Keller, Bettina G. ChemPhysChem, Vol. 18, Issue 23 https://doi.org/10.1002/cphc.201700995	journal	November 2017
Inhibition of Human Immunodeficiency Virus Type 1 Replication in Human Cells by Debio-025, a Novel Cyclophilin Binding Agent Ptak, Roger G.; Gallay, Philippe A.; Jochmans, Dirk Antimicrobial Agents and Chemotherapy, Vol. 52, Issue 4 https://doi.org/10.1128/AAC.01324-07	journal	April 2008
Cyclic Peptides in Pipeline: What Future for These Great Molecules? Costa, Lia; Sousa, Emília; Fernandes, Carla Pharmaceuticals, Vol. 16, Issue 7 https://doi.org/10.3390/ph16070996	journal	July 2023
Lead- and drug-like compounds: the rule-of-five revolution Lipinski, Christopher A. Drug Discovery Today: Technologies, Vol. 1, Issue 4 https://doi.org/10.1016/j.ddtec.2004.11.007	journal	December 2004
Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings 1PII of original article: S0169-409X(96)00423-1. The article was originally published in Advanced Drug Delivery Reviews 23 (1997) 3–25. 1 Lipinski, Christopher A.; Lombardo, Franco; Dominy, Beryl W. Advanced Drug Delivery Reviews, Vol. 46, Issue 1-3 https://doi.org/10.1016/S0169-409X(00)00129-0	journal	March 2001
Peptide/protein-based macrocycles: from biological synthesis to biomedical applications Wu, Wen-Hao; Guo, Jianwen; Zhang, Longshuai RSC Chemical Biology, Vol. 3, Issue 7 https://doi.org/10.1039/D1CB00246E	journal	January 2022
A well-behaved electrostatic potential based method using charge restraints for deriving atomic charges: the RESP model Bayly, Christopher I.; Cieplak, Piotr; Cornell, Wendy The Journal of Physical Chemistry, Vol. 97, Issue 40 https://doi.org/10.1021/j100142a004	journal	October 1993
Atomic View of Aqueous Cyclosporine A: Unpacking a Decades-Old Mystery Limbach, Miranda N.; Antevska, Aleksandra; Oluwatoba, Damilola S. Journal of the American Chemical Society, Vol. 144, Issue 28 https://doi.org/10.1021/jacs.2c01743	journal	July 2022
Structure of human cyclophilin and its binding site for cyclosporin A determined by X-ray crystallography and NMR spectroscopy Kallen, Jörg; Spitzfaden, Claus; Zurini, Mauro G. M. Nature, Vol. 353, Issue 6341 https://doi.org/10.1038/353276a0	journal	September 1991
Macrocycles in new drug discovery Mallinson, Jamie; Collins, Ian Future Medicinal Chemistry, Vol. 4, Issue 11 https://doi.org/10.4155/fmc.12.93	journal	July 2012
Cyclosporin H is a potent and selective competitive antagonist of human basophil activation by N-formyl-methionyl-leucyl-phenylalanine☆, ☆☆, ★, ★★ Depaulis, A.; Ciccarelli, A.; Decrescenzo, G. Journal of Allergy and Clinical Immunology, Vol. 98, Issue 1 https://doi.org/10.1016/S0091-6749(96)70237-3	journal	July 1996
Molecular Mechanisms of Immunosuppression by Cyclosporins Zenke, Gerhard; Baumann, GÖTz; Wenger, Roland Annals of the New York Academy of Sciences, Vol. 685, Issue 1 https://doi.org/10.1111/j.1749-6632.1993.tb35882.x	journal	June 1993
X-ray Structure of a Monomeric Cyclophilin A-Cyclosporin A Crystal Complex at 2·1 Å Resolution Mikol, Vincent; Kallen, Jörg; Pflügl, Gaston Journal of Molecular Biology, Vol. 234, Issue 4 https://doi.org/10.1006/jmbi.1993.1664	journal	December 1993
Cyclosporins: Structure−Activity Relationships for the Inhibition of the Human MDR1 P-Glycoprotein ABC Transporter Loor, Francis; Tiberghien, Françoise; Wenandy, Tom Journal of Medicinal Chemistry, Vol. 45, Issue 21 https://doi.org/10.1021/jm0109863	journal	September 2002
Cyclic peptide drugs approved in the last two decades (2001–2021) Zhang, Huiya; Chen, Shiyu RSC Chemical Biology, Vol. 3, Issue 1 https://doi.org/10.1039/D1CB00154J	journal	January 2022
Cyclosporine: A Review Tedesco, Dustin; Haragsim, Lukas Journal of Transplantation, Vol. 2012 https://doi.org/10.1155/2012/230386	journal	January 2012
Inhibition of SARS-CoV-2 Infection by the Cyclophilin Inhibitor Alisporivir (Debio 025) Softic, Laurent; Brillet, Rozenn; Berry, François Antimicrobial Agents and Chemotherapy, Vol. 64, Issue 7 https://doi.org/10.1128/AAC.00876-20	journal	June 2020
Two new cyclosporin folds observed in the structures of the immunosuppressant cyclosporin G and the formyl peptide receptor antagonist cyclosporin H at ultra-high resolution Potter, Brian; Palmer, Rex A.; Withnall, Robert Organic & Biomolecular Chemistry, Vol. 1, Issue 9 https://doi.org/10.1039/b210086j	journal	April 2003
ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB Maier, James A.; Martinez, Carmenza; Kasavajhala, Koushik Journal of Chemical Theory and Computation, Vol. 11, Issue 8 https://doi.org/10.1021/acs.jctc.5b00255	journal	July 2015
Infrared multiple photon dissociation spectroscopy of trapped ions Polfer, Nick C. Chemical Society Reviews, Vol. 40, Issue 5 https://doi.org/10.1039/c0cs00171f	journal	January 2011
The non-immunosuppressive cyclosporin DEBIO-025 is a potent inhibitor of hepatitis C virus replicationin vitro Paeshuyse, Jan; Kaul, Artur; De Clercq, Erik Hepatology, Vol. 43, Issue 4 https://doi.org/10.1002/hep.21102	journal	January 2006
Ultrahigh frequency and microwave relaxation of lithium perchlorate in tetrahydrofuran Farber, Herman; Petrucci, Sergio The Journal of Physical Chemistry, Vol. 79, Issue 12 https://doi.org/10.1021/j100579a015	journal	June 1975
Dielectric relaxation of electrolyte solutions in acetonitrile Barthel, J.; Kleebauer, M.; Buchner, R. Journal of Solution Chemistry, Vol. 24, Issue 1 https://doi.org/10.1007/BF00973045	journal	January 1995
The dielectric properties of formamide, ethanediol and methanol Jordan, B. P.; Sheppard, R. J.; Szwarnowski, S. Journal of Physics D: Applied Physics, Vol. 11, Issue 5 https://doi.org/10.1088/0022-3727/11/5/013	journal	April 1978
Extension of the classical classification of β-turns de Brevern, Alexandre G. Scientific Reports, Vol. 6, Issue 1 https://doi.org/10.1038/srep33191	journal	September 2016
Macrocycles Are Great Cycles: Applications, Opportunities, and Challenges of Synthetic Macrocycles in Drug Discovery Marsault, Eric; Peterson, Mark L. Journal of Medicinal Chemistry, Vol. 54, Issue 7 https://doi.org/10.1021/jm1012374	journal	April 2011
Strategies for targeting undruggable targets Zhang, Gong; Zhang, Juan; Gao, Yuting Expert Opinion on Drug Discovery, Vol. 17, Issue 1 https://doi.org/10.1080/17460441.2021.1969359	journal	August 2021
The exploration of macrocycles for drug discovery — an underexploited structural class Driggers, Edward M.; Hale, Stephen P.; Lee, Jinbo Nature Reviews Drug Discovery, Vol. 7, Issue 7 https://doi.org/10.1038/nrd2590	journal	July 2008
Experimental nephrotoxicity, hepatotoxicity and pharmacokinetics of cyclosporin G versus cyclosporin A Burdmann, Emmanuel A.; Andoh, Takeshi F.; Rosen, Seymour Kidney International, Vol. 45, Issue 3 https://doi.org/10.1038/ki.1994.92	journal	March 1994
Observation of Conformational Exchange in Cyclosporin in Media of Varying Polarity by NMR Spectroscopy Efimov, Sergey; Zgadzay, Yuriy; Klochkov, Vladimir Applied Magnetic Resonance, Vol. 45, Issue 11 https://doi.org/10.1007/s00723-014-0602-y	journal	October 2014
Debio 025, a Cyclophilin Binding Molecule, Is Highly Efficient in Clearing Hepatitis C Virus (HCV) Replicon-Containing Cells When Used Alone or in Combination with Specifically Targeted Antiviral Therapy for HCV (STAT-C) Inhibitors Coelmont, Lotte; Kaptein, Suzanne; Paeshuyse, Jan Antimicrobial Agents and Chemotherapy, Vol. 53, Issue 3 https://doi.org/10.1128/AAC.00939-08	journal	March 2009
R.E.D. Server: a web service for deriving RESP and ESP charges and building force field libraries for new molecules and molecular fragments Vanquelef, Enguerran; Simon, Sabrina; Marquant, Gaelle Nucleic Acids Research, Vol. 39, Issue suppl_2 https://doi.org/10.1093/nar/gkr288	journal	May 2011
FDA-Approved Small Molecules in 2022: Clinical Uses and Their Synthesis Benedetto Tiz, Davide; Bagnoli, Luana; Rosati, Ornelio Pharmaceutics, Vol. 14, Issue 11 https://doi.org/10.3390/pharmaceutics14112538	journal	November 2022
Applications of Infrared Multiple Photon Dissociation (IRMPD) to the Detection of Posttranslational Modifications Maitre, Philippe; Scuderi, Debora; Corinti, Davide Chemical Reviews, Vol. 120, Issue 7 https://doi.org/10.1021/acs.chemrev.9b00395	journal	December 2019
The cyclophilin inhibitor alisporivir prevents hepatitis C virus-mediated mitochondrial dysfunction Quarato, Giovanni; D'Aprile, Annamaria; Gavillet, Bruno Hepatology, Vol. 55, Issue 5 https://doi.org/10.1002/hep.25514	journal	March 2012
Structural Flexibility of Cyclosporine A Is Mediated by Amide Cis–Trans Isomerization and the Chameleonic Roles of Calcium Gray, Amber L. H.; Steren, Carlos A.; Haynes, Isaac W. The Journal of Physical Chemistry B, Vol. 125, Issue 5 https://doi.org/10.1021/acs.jpcb.0c11152	journal	February 2021
Improving Conformer Generation for Small Rings and Macrocycles Based on Distance Geometry and Experimental Torsional-Angle Preferences Wang, Shuzhe; Witek, Jagna; Landrum, Gregory A. Journal of Chemical Information and Modeling, Vol. 60, Issue 4 https://doi.org/10.1021/acs.jcim.0c00025	journal	March 2020
The Challenge of Drugging Undruggable Targets in Cancer: Lessons Learned from Targeting BCL-2 Family Members Verdine, Gregory L.; Walensky, Loren D. Clinical Cancer Research, Vol. 13, Issue 24 https://doi.org/10.1158/1078-0432.CCR-07-2184	journal	December 2007
Ranking High Affinity Ligands of Low Solubility by NMR Spectroscopy Landrieu, Isabelle; Hanoulle, Xavier; Fritzinger, Bernd ACS Medicinal Chemistry Letters, Vol. 2, Issue 6 https://doi.org/10.1021/ml200039u	journal	April 2011

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37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
cyclosporine
cyclic ion mobility spectrometry
nuclear magnetic resonance
molecular dynamics
conformational heterogeneity
membrane permeability

Title: Taming Conformational Heterogeneity on Ion Racetrack to Unveil Principles that Drive Membrane Permeation of Cyclosporines

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