| Título | Delocalized quinolinium-macrocyclic peptides, an atypical chemotype for CNS penetration |
|---|---|
| Autores | 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. |
| Publicación externa | No |
| Medio | Sci. Adv. |
| Alcance | Article |
| Naturaleza | Científica |
| Cuartil JCR | 1 |
| Cuartil SJR | 1 |
| Web | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85198495525&doi=10.1126%2fsciadv.ado3501&partnerID=40&md5=1b19e1550c7fc1eede291f54b47f3dc8 |
| Fecha de publicacion | 10/07/2024 |
| ISI | 001280159000014 |
| Scopus Id | 2-s2.0-85198495525 |
| 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. |
| Palabras clave | Animals; Brain; Central Nervous System; Crystallography, X-Ray; Cyclosporine; Humans; Mice; Peptides; Quinolinium Compounds; Biosynthesis; Drug products; X ray crystallography; cyclosporine; peptide; quinoline derivative; Atypicals; Central nervous systems; Chemotypes; Cyclophilin; Delocalizations; Macrocyclics; Molecular targets; Synthesised; System access; animal; brain; central nervous system; chemistry; drug effect; human; metabolism; mouse; X ray crystallography; Positive ions |
| Miembros de la Universidad Loyola |