Delocalized quinolinium-macrocyclic peptides, an atypical chemotype for CNS penetration
Delocalized quinolinium-macrocyclic peptides, an atypical chemotype for CNS penetration
Macrocyclic drugs can address an increasing range of molecular targets but enabling central nervous system (CNS) access to these drugs has been viewed as an intractable problem. We designed and synthesized a series of quinolinium-modified cyclosporine derivatives targeted to the mitochondrial cyclophilin D protein. Modification of the cation to enable greater delocalization was confirmed by x-ray crystallography of the cations. Critically, greater delocalization improved brain concentrations. Assessment of the compounds in preclinical assays and for pharmacokinetics identified a molecule JP1-138 with at least 20 times the brain levels of a non-delocalized compound or those reported for cyclosporine. Levels were maintained over 24 hours together with low hERG potential. The paradigm outlined here could have widespread utility in the treatment of CNS diseases.
Pingitore, Valeria
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Pancholi, Jessica
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Hornsby, Thomas W.
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Warne, Justin
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Pryce, Gareth
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McCormick, Laura J.
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Hill, Julia
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Bhosale, Gauri
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Peng, Jing
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Newton, Lydia S.
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Towers, Greg J.
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Coles, Simon J.
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Chan, Ah Wing Edith
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Duchen, Michael R.
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Szabadkai, Gyorgy
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Baker, David
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Selwood, David L.
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Pingitore, Valeria
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Pancholi, Jessica
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Hornsby, Thomas W.
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Warne, Justin
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Pryce, Gareth
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McCormick, Laura J.
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Hill, Julia
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Bhosale, Gauri
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Peng, Jing
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Newton, Lydia S.
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Towers, Greg J.
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Coles, Simon J.
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Chan, Ah Wing Edith
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Duchen, Michael R.
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Szabadkai, Gyorgy
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Baker, David
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Selwood, David L.
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Pingitore, Valeria, Pancholi, Jessica, Hornsby, Thomas W., Warne, Justin, Pryce, Gareth, McCormick, Laura J., Hill, Julia, Bhosale, Gauri, Peng, Jing, Newton, Lydia S., Towers, Greg J., Coles, Simon J., Chan, Ah Wing Edith, Duchen, Michael R., Szabadkai, Gyorgy, Baker, David and Selwood, David L.
(2024)
Delocalized quinolinium-macrocyclic peptides, an atypical chemotype for CNS penetration.
Science Advances, 10 (28), [ado3501].
(doi:10.1126/sciadv.ado3501).
Abstract
Macrocyclic drugs can address an increasing range of molecular targets but enabling central nervous system (CNS) access to these drugs has been viewed as an intractable problem. We designed and synthesized a series of quinolinium-modified cyclosporine derivatives targeted to the mitochondrial cyclophilin D protein. Modification of the cation to enable greater delocalization was confirmed by x-ray crystallography of the cations. Critically, greater delocalization improved brain concentrations. Assessment of the compounds in preclinical assays and for pharmacokinetics identified a molecule JP1-138 with at least 20 times the brain levels of a non-delocalized compound or those reported for cyclosporine. Levels were maintained over 24 hours together with low hERG potential. The paradigm outlined here could have widespread utility in the treatment of CNS diseases.
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sciadv.ado3501
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Accepted/In Press date: 4 June 2024
e-pub ahead of print date: 10 July 2024
Identifiers
Local EPrints ID: 496506
URI: http://eprints.soton.ac.uk/id/eprint/496506
ISSN: 2375-2548
PURE UUID: 1dc91e40-3776-4d17-b296-aff194fbdc95
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Date deposited: 17 Dec 2024 17:36
Last modified: 18 Dec 2024 03:08
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Contributors
Author:
Valeria Pingitore
Author:
Jessica Pancholi
Author:
Thomas W. Hornsby
Author:
Justin Warne
Author:
Gareth Pryce
Author:
Julia Hill
Author:
Gauri Bhosale
Author:
Jing Peng
Author:
Lydia S. Newton
Author:
Greg J. Towers
Author:
Ah Wing Edith Chan
Author:
Michael R. Duchen
Author:
Gyorgy Szabadkai
Author:
David Baker
Author:
David L. Selwood
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