Applying the Retro-Enantio Approach To Obtain a Peptide Capable of Overcoming the Blood-Brain Barrier

The blood–brain barrier (BBB) is a formidable physical and enzymatic barrier that tightly controls the passage of molecules from the blood to the brain. In fact, less than 2 % of all potential neurotherapeutics are able to cross it. Here, by applying the retro‐enantio approach to a peptide that targets the transferrin receptor, a full protease‐resistant peptide with the capacity to act as a BBB shuttle was obtained and thus enabled the transport of a variety of cargos into the central nervous system. Jumping hurdles: The retro‐enantio approach has been applied to a peptide that targets the transferrin receptor. The stability and permeability of the peptide across the blood–brain barrier (BBB) were notably increased. This new protease‐resistant peptide was tested as a BBB shuttle, and it does facilitate the transport of cargo across the BBB, both in vitro and in vivo, as demonstrated by intravital microscopy in living mice.