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 cyclop...
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| Veröffentlicht in: | Science advances 2024-07, Vol.10 (28), p.eado3501 |
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| creator | 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 Selwood, David L |
| description | 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. |
| doi_str_mv | 10.1126/sciadv.ado3501 |
| format | Article |
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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.</description><identifier>ISSN: 2375-2548</identifier><identifier>EISSN: 2375-2548</identifier><identifier>DOI: 10.1126/sciadv.ado3501</identifier><identifier>PMID: 38985859</identifier><language>eng</language><publisher>United States: American Association for the Advancement of Science</publisher><subject>Animals ; Biochemistry ; Brain - drug effects ; Brain - metabolism ; Central Nervous System - drug effects ; Central Nervous System - metabolism ; Crystallography, X-Ray ; Cyclosporine - chemistry ; Cyclosporine - pharmacokinetics ; Humans ; Mice ; Peptides - chemistry ; Peptides - pharmacokinetics ; Physical and Materials Sciences ; Quinolinium Compounds - chemistry ; Quinolinium Compounds - pharmacokinetics ; SciAdv r-articles</subject><ispartof>Science advances, 2024-07, Vol.10 (28), p.eado3501</ispartof><rights>Copyright © 2024 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. 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Distributed under a Creative Commons Attribution License 4.0 (CC BY). 2024 The Authors</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c276t-f6077193a0529b92917ddd0919bdf9e5644dc53fe7234a645ce36940387c15a03</cites><orcidid>0009-0002-1706-8346 ; 0000-0001-8414-9272 ; 0000-0002-6817-5064 ; 0000-0002-3006-3577 ; 0000-0003-1669-0141 ; 0000-0002-8872-8711 ; 0009-0001-0997-9628 ; 0000-0003-2321-6296 ; 0009-0007-4604-6601 ; 0000-0002-7707-0264 ; 0000-0003-2548-4294 ; 0000-0002-6634-4717</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11235165/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11235165/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38985859$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pingitore, Valeria</creatorcontrib><creatorcontrib>Pancholi, Jessica</creatorcontrib><creatorcontrib>Hornsby, Thomas W</creatorcontrib><creatorcontrib>Warne, Justin</creatorcontrib><creatorcontrib>Pryce, Gareth</creatorcontrib><creatorcontrib>McCormick, Laura J</creatorcontrib><creatorcontrib>Hill, Julia</creatorcontrib><creatorcontrib>Bhosale, Gauri</creatorcontrib><creatorcontrib>Peng, Jing</creatorcontrib><creatorcontrib>Newton, Lydia S</creatorcontrib><creatorcontrib>Towers, Greg J</creatorcontrib><creatorcontrib>Coles, Simon J</creatorcontrib><creatorcontrib>Chan, Ah Wing Edith</creatorcontrib><creatorcontrib>Duchen, Michael R</creatorcontrib><creatorcontrib>Szabadkai, Gyorgy</creatorcontrib><creatorcontrib>Baker, David</creatorcontrib><creatorcontrib>Selwood, David L</creatorcontrib><title>Delocalized quinolinium-macrocyclic peptides, an atypical chemotype for CNS penetration</title><title>Science advances</title><addtitle>Sci Adv</addtitle><description>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. 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| subjects | Animals Biochemistry Brain - drug effects Brain - metabolism Central Nervous System - drug effects Central Nervous System - metabolism Crystallography, X-Ray Cyclosporine - chemistry Cyclosporine - pharmacokinetics Humans Mice Peptides - chemistry Peptides - pharmacokinetics Physical and Materials Sciences Quinolinium Compounds - chemistry Quinolinium Compounds - pharmacokinetics SciAdv r-articles |
| title | Delocalized quinolinium-macrocyclic peptides, an atypical chemotype for CNS penetration |
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