Molecular Shuttle Could Help Drugs Find A Way Into The Brain

Picking the right stereoisomer of a peptide might help get small drugs into the brain more easily, according to a new study led by a team from the Institute for Research in Biomedicine, in Barcelona (J. Am. Chem. Soc. 2015, DOI: 10.1021/jacs.5b02050).

Meritxell Teixidó, Ernest Giralt, and colleagues were searching for peptides water-soluble enough to be carried through the blood but lipophilic enough to get across the fiendishly hard-to-cross blood-brain barrier (BBB). This dense layer of cells lines the brain’s capillaries and prevents most compounds from passing into the brain from the bloodstream. The team wanted to use the peptides as shuttles to carry small drugs into the brain as the peptides diffuse through the lipid bilayers of the cell walls that make up the BBB.

Previously, the group had designed a shuttle based on N-methylphenylalanine (N- MePhe), which was good at crossing the BBB, but was poorly water-soluble. To improve upon it, they designed a peptide made of four cis-3-phenylpyrrolidine-2-carboxylic acid (PhPro) molecules and measured its ability to carry two cargo molecules— L-DOPA and nipecotic acid—across a lab-made membrane that acts as an artificial BBB. The new shuttle carried sevenfold more cargo across the membrane than N-MePhe and was 1,000 times as water-soluble.

Furthermore, making the peptides out of different combinations of PhPro enantiomers revealed a surprise. Out of a library of 16 such shuttles, “there were some combinations of enantiomeric pairs that crossed differently” from others, Teixidó says. This could be because the crowded aromatic rings in PhPro make some combinations easier than others to squeeze through the tightly packed cells in the BBB, Teixidó suggests. Other peptide shuttles could be improved with the same enantiomer screening approach, she says, but whether the drugs will work in the brain when bound to the shuttles remains to be seen.