Peptides for blood-brain barrier transmigration and drug delivery - novel therapies for the central nervous system CNS

Funder

Organizational Unit

Publications

Antibody approaches to treat brain diseases

Publication . Neves, Vera; Silva, Frederico Aires da; Real, Sofia Corte; Castanho, Miguel A. R. B.

Recombinant antibodies are an emerging class of therapeutics with substantial promise to treat central nervous system (CNS) diseases such as Alzheimer's, Parkinson's, stroke, and brain cancers. However, poor blood–brain barrier (BBB) permeability hinders the progress of antibody therapies for conditions in which the target is located in the brain. Nonetheless, antibodies can nowa-days be engineered to enhance their therapeutic applications and translocation of the BBB using the natural portals of the brain. This paper reviews advances in the development and engineering of therapeutic BBB-crossing antibodies and their high potential for treatment of CNS disorders.

2016Journal article

Restricted access

A new noncanonical anionic peptide that translocates a cellular blood-brain barrier model

Publication . Neves Coelho, Sara; Eleutério, Rute P.; Enguita, Francisco J.; Neves, Vera; Castanho, Miguel A. R. B.

The capacity to transport therapeutic molecules across the blood–brain barrier (BBB) represents a breakthrough in the development of tools for the treatment of many central nervous system (CNS)-associated diseases. The BBB, while being protective against infectious agents, hinders the brain uptake of many drugs. Hence, finding safe shuttles able to overcome the BBB is of utmost importance. Herein, we identify a new BBB-translocating peptide with unique properties. For years it was thought that cationic sequences were mandatory for a cell-penetrating peptide (CPP) to achieve cellular internalization. Despite being anionic at physiological pH, PepNeg (sequence (SGTQEEY) is an efficient BBB translocator that is able to carry a large cargo (27 kDa), while maintaining BBB integrity. In addition, PepNeg is able to use two distinct methods of translocation, energy-dependent and -independent, suggesting that direct penetration might occur when low concentrations of peptide are presented to cells. The discovery of this new anionic trans-BBB peptide allows the development of new delivery systems to the CNS and contributes to the need to rethink the role of electrostatic attraction in BBB-translocation

2017Journal article

Open access

Novel peptides derived from dengue virus capsid protein translocate reversibly the blood−brain barrier through a receptor-free mechanism

Publication . Neves, Vera; Silva, Frederico Aires da; Morais, Maurício; Gano, Lurdes; Ribeiro, Elisabete; Pinto, Antónia; Aguiar, Sandra; Gaspar, Diana; Fernandes, Célia; Correia, João D. G.; Castanho, Miguel A. R. B.

The delivery of therapeutic molecules to the central nervous system is hampered by poor delivery across the blood-brain barrier (BBB). Several strategies have been proposed to enhance transport into the brain, including invasive techniques and receptor-mediated transport (RMT). Both approaches have several drawbacks, such as BBB disruption, receptor saturation, and off-target effects, raising safety issues. Herein, we show that specific domains of Dengue virus type 2 capsid protein (DEN2C) can be used as trans-BBB peptide vectors. Their mechanism of translocation is receptor-independent and consistent with adsorptive-mediated transport (AMT). One peptide in particular, named PepH3, reaches equilibrium distribution concentrations across the BBB in less than 24 h in a cellular in vitro assay. Importantly, in vivo biodistribution data with radiolabeled peptide derivatives show high brain penetration. In addition, there is fast clearance from the brain and high levels of excretion, showing that PepH3 is a very good candidate to be used as a peptide shuttle taking cargo in and out of the brain.

2017Journal article

Restricted access