Pharmacoproteomics of Brain Barrier Transporters and Substrate Design for the Brain Targeted Drug Delivery

• Published in: Pharmaceutical research 2022-07, Vol.39 (7), p.1363-1392
• Main Authors: Huttunen, Kristiina M., Terasaki, Tetsuya, Urtti, Arto, Montaser, Ahmed B., Uchida, Yasuo
• Format: Article
• Language: English
• Subjects: Amino acids; Arachnoid; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Blood circulation; Blood-brain barrier; Brain research; Breast cancer; Central nervous system; Cerebrospinal fluid; Computational neuroscience; Drug delivery; Drug delivery systems; Drug development; Drugs; Expert Review; Medical Law; Molecular dynamics; Nervous system; Permeability; Pharmaceuticals; Pharmacokinetics; Pharmacology/Toxicology; Pharmacy; Protein binding; Protein expression; Protein transport; Proteins; Simulation; Simulation methods; Spinal cord; Vehicles
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-022-03193-2

One of the major reasons why central nervous system (CNS)-drug development has been challenging in the past, is the barriers that prevent substances entering from the blood circulation into the brain. These barriers include the blood-brain barrier (BBB), blood-spinal cord barrier (BSCB), blood-cerebrospinal fluid barrier (BCSFB), and blood-arachnoid barrier (BAB), and they differ from each other in their transporter protein expression and function as well as among the species. The quantitative expression profiles of the transporters in the CNS-barriers have been recently revealed, and in this review, it is described how they affect the pharmacokinetics of compounds and how these expression differences can be taken into account in the prediction of brain drug disposition in humans, an approach called pharmacoproteomics . In recent years, also structural biology and computational resources have progressed remarkably, enabling a detailed understanding of the dynamic processes of transporters. Molecular dynamics simulations (MDS) are currently used commonly to reveal the conformational changes of the transporters and to find the interactions between the substrates and the protein during the binding, translocation in the transporter cavity, and release of the substrate on the other side of the membrane. The computational advancements have also aided in the rational design of transporter-utilizing compounds, including prodrugs that can be actively transported without losing potency towards the pharmacological target. In this review, the state-of-art of these approaches will be also discussed to give insights into the transporter-mediated drug delivery to the CNS.