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
Dongjae LeeJiwon Seo

Abstract

A macrocyclic peptide scaffold with well-established structure-property relationship is desirable for tackling undruggable targets. Here, we adopted a natural macrocycle, cyclosporin O (CsO) and its derivatives (CP1-3), and evaluated the impact of conformation on membrane permeability, cyclophilin A (CypA) binding, and the pharmacokinetic (PK) profile. In nonpolar media, CsO showed a similar conformation to cyclosporin A (CsA), a well-known chameleonic macrocycle, but less chameleonic behavior in a polar environment. The weak chameleonicity of CsO resulted in decreased membrane permeability; however, the more rigid conformation of CsO was not detrimental to its PK profile. CsO exhibited a higher plasma concentration than CsA, which resulted from minimal CypA binding and lower accumulation in red blood cells and moderate oral bioavailability (F = 12%). Our study aids understanding of CsO, a macrocyclic peptide that is less explored than CsA but with greater potential for diversity generation and rational design.

References

Dec 20, 1993·Journal of Molecular Biology·V MikolM D Walkinshaw
Oct 24, 2001·The Journal of Organic Chemistry·Prakash RamanDaniel H. Rich
Jan 5, 2002·Journal of Biomolecular NMR·T Cierpicki, J Otlewski
May 31, 2002·Journal of Medicinal Chemistry·Daniel F VeberKenneth D Kopple
Dec 4, 2003·Bioorganic & Medicinal Chemistry Letters·Michel EversSerge Mignani
Apr 3, 2004·Nature Reviews. Drug Discovery·Michelle R Arkin, James A Wells
Apr 15, 2004·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·R Neslihan Gursoy, Simon Benita
Apr 2, 2005·Biological & Pharmaceutical Bulletin·Young-Joo LeeChang-Koo Shim
Feb 24, 2006·Journal of the American Chemical Society·Taha RezaiR Scott Lokey
Oct 30, 2007·The Journal of Organic Chemistry·Subramanyam J TantryVommina Venkata Sureshbabu
Mar 12, 2009·Protein and Peptide Letters·Vommina Venkata SureshbabuGovindappa Nagendra
Sep 29, 2011·Nature Chemical Biology·Tina R WhiteR Scott Lokey
Jun 29, 2012·Journal of the American Chemical Society·Johannes G BeckHorst Kessler
Jul 27, 2012·Expert Reviews in Molecular Medicine·Matthew C Smith, Jason E Gestwicki
Sep 21, 2013·Journal of Medicinal Chemistry·Fabrizio Giordanetto, Jan Kihlberg
Sep 1, 2010·Toxicological Research·Jinhwa Lee
Jul 21, 2014·Nature Chemical Biology·Elizabeth A VillarAdrian Whitty
Jul 21, 2014·Nature Chemical Biology·Jason GavenonisJoshua A Kritzer
Sep 16, 2014·Angewandte Chemie·Daniel S NielsenDavid P Fairlie
Sep 23, 2014·Chemistry & Biology·Michelle R ArkinJames A Wells
Sep 23, 2014·Chemistry & Biology·Bradley Croy DoakJan Kihlberg
Oct 8, 2014·Angewandte Chemie·Timothy A HillDavid P Fairlie
Nov 25, 2014·Proceedings of the National Academy of Sciences of the United States of America·Conan K WangDavid J Craik
Dec 17, 2014·Bioinformatics·Woonghee LeeJohn L Markley
Dec 18, 2014·Journal of the American Chemical Society·William M HewittR Scott Lokey
Apr 29, 2015·Chemistry : a European Journal·Udaya Kiran MarelliHorst Kessler
Jun 13, 2015·Future Medicinal Chemistry·Christopher L AhlbachR Scott Lokey
Sep 5, 2015·Chembiochem : a European Journal of Chemical Biology·Daniel S NielsenDavid P Fairlie
Oct 13, 2015·Journal of Medicinal Chemistry·Bradley C DoakJan Kihlberg
Feb 20, 2016·Drug Discovery Today·Adrian WhittySandor Vajda
Jul 9, 2016·Journal of Chemical Information and Modeling·Jagna WitekSereina Riniker
Aug 27, 2016·ACS Medicinal Chemistry Letters·Joshua SchwochertR Scott Lokey

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Citations

Sep 4, 2021·Journal of Medicinal Chemistry·Karen M CorbettDavid K Chalmers

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