Novel Peptides Derived from Dengue Virus Capsid Protein Translocate Reversibly the Blood–Brain Barrier through a Receptor-Free Mechanism
- Vera Neves
, - Frederico Aires-da-Silva ,
- Maurício Morais ,
- Lurdes Gano ,
- Elisabete Ribeiro ,
- Antónia Pinto ,
- Sandra Aguiar ,
- Diana Gaspar ,
- Célia Fernandes ,
- João D. G. Correia , and
- Miguel A. R. B. Castanho
Abstract
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.
Cited By
This article is cited by 6 publications.
- Yamir Islam, Andrew G Leach, Jayden Smith, Stefano Pluchino, Christopher R Coxonl, Muttuswamy Sivakumaran, James Downing, Amos A Fatokun, Meritxell Teixidò, Touraj Ehtezazi. Peptide based drug delivery systems to the brain. Nano Express 2020, 1 (1) , 012002. https://doi.org/10.1088/2632-959X/ab9008
- Marco Cavaco, Diana Gaspar, Miguel ARB Castanho, Vera Neves. Antibodies for the Treatment of Brain Metastases, a Dream or a Reality?. Pharmaceutics 2020, 12 (1) , 62. https://doi.org/10.3390/pharmaceutics12010062
- Verònica Casadó-Anguera, Antoni Cortés, Vicent Casadó, Estefanía Moreno. Targeting the receptor-based interactome of the dopamine D1 receptor: looking for heteromer-selective drugs. Expert Opinion on Drug Discovery 2019, 14 (12) , 1297-1312. https://doi.org/10.1080/17460441.2019.1664469
- Maria Gallo, Sira Defaus, David Andreu. 1988–2018: Thirty years of drug smuggling at the nano scale. Challenges and opportunities of cell-penetrating peptides in biomedical research. Archives of Biochemistry and Biophysics 2019, 661 , 74-86. https://doi.org/10.1016/j.abb.2018.11.010
- Sara Neves-Coelho, Rute Eleutério, Francisco Enguita, Vera Neves, Miguel Castanho. A New Noncanonical Anionic Peptide That Translocates a Cellular Blood–Brain Barrier Model. Molecules 2017, 22 (10) , 1753. https://doi.org/10.3390/molecules22101753
- Handan Acar, Jeffrey M. Ting, Samanvaya Srivastava, James L. LaBelle, Matthew V. Tirrell. Molecular engineering solutions for therapeutic peptide delivery. Chemical Society Reviews 2017, 46 (21) , 6553-6569. https://doi.org/10.1039/C7CS00536A