Delocalized Quinolinium-macrocyclic Peptides, an Atypical Chemotype for CNS Penetration

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2024 Jul 10

PMID 38985859

Authors

Valeria Pingitore

Jessica Pancholi

Thomas W Hornsby

Justin Warne

Gareth Pryce

Laura J McCormick

Julia Hill

Gauri Bhosale

Jing Peng

Lydia S Newton

Greg J Towers

Simon J Coles

Ah Wing Edith Chan

Michael R Duchen

Gyorgy Szabadkai

David Baker

David L Selwood

Affiliations

Soon will be listed here.

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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