Brain shuttle peptides derived from natural proteins

Blood-brain barrier (BBB) is the primary physiological barrier that regulates the movement of substances between the systemic circulation and the brain. Its unique structure, based on specialized endothelial cells, allows tight regulation of central nervous system (CNS) homeostasis and at the same time is the main hurdle in the modern medicine to treat neurological conditions. Many promising in vitro drugs become ineffective in vivo due to BBB restrictive permeability. However, in the last two decades, a variety of molecules, mainly peptide-based and named brain shuttle peptides, were able to ferry various payloads (small molecules, proteins, antibodies etc.) into the brain. Therefore, these shuttles could become key future therapeutics to fight various CNS conditions. Brain shuttle peptides are part of a larger family of cell-penetrating peptides (CPPs) that utilize different modes of membrane transport with predominance of adsorptive-mediated transcytosis (AMT) and receptor-mediated transcytosis (RMT). The discovery and development process of new brain shuttle peptides is mainly guided by using rational design and bioinformatics approaches focusing mostly on proteins from natural sources (viruses, amphibians, reptiles and mammals). In the last years, the virus- and mammal-derived brain shuttle peptides have been gaining increased attention due to their superb translocation capacity, low immunogenicity and toxicity, good stability and ease of preparation. Here, we will focus on the most prominent brain shuttle peptides of viral and animal origin with documented BBB crossing capabilities, discussing their mechanisms of translocation and therapeutic applications. Notably, the two brain shuttle peptides that have successfully progressed to clinical trials thus far originate from a viral source (TAT) and a mammalian source (Angiopep-2).