Dienstag, 21. November 2017, 11:00 - 12:30 iCal
João Domingos Galamba Correia
Centro de Ciências e Technologias Nucleares,
Instituto Superior Téchnico, Universidade de Lisboa
"Peptides derived from Dengue virus type 2 capsid pro-tein translocate the blood brain barrier: Radiomet-alation and biological evaluation”
Kleiner Hörsaal 4 der Fakultät für Chemie
Währinger Straße 42, 1090 Wien
Vortrag
João Domingos Galamba Correia /
Centro de Ciências e Technologias Nucleares,
Instituto Superior Téchnico, Universidade de Lisboa
„Peptides derived from Dengue virus type 2 capsid pro-tein translocate the blood brain barrier: Radiomet-alation and biological evaluation”
The low success rate of central nervous system (CNS)-targeted treatments is strongly related to the poor delivery to the brain, being the blood-brain barrier (BBB) the main hurdle for effective CNS drug delivery.[1] Small lipophilic molecules cross the BBB by passive diffusion whereas glucose and amino acids use carriers. However, around 98 % of small molecules and nearly all large molecules, such as recombinant proteins or gene-based medicines, do not cross the BBB.[2] The few large molecules that translocate the BBB are transported via receptor-mediated transcytosis (RMT), such as the case of transferrin, or adsorptive-mediated transcytosis (AMT). New approaches that overcome the limitations of RMT are urgently needed, being AMT a suitable alternative. Peptide vectors for AMT are typically cationic and may contain amphipathic domains. They include, among others, the trans-activating transcrip-tional activator from the human immunodeficiency virus 1 and the third helix of Antennapedia homeodomain. These peptides deliver different cargos across a variety of endothelial cells.[3] A recent study has also shown the uptake of angiopep-2 paclitaxel conjugate into the brain with improved delivery to brain metastases of breast cancer.[4]
In this presentation I will report on the synthesis, characterization, radiometalation (99mTc and 67Ga) and biological evaluation of novel peptide conjugates combining a specific bifunctional chelator and peptides derived from specific domains of Dengue virus type 2 capsid protein (DEN2C). It will be demonstrated, through in vitro and in vivo assays, that the selected peptides can be used as trans-BBB peptide vectors, being their mechanism of translocation consistent with AMT. More importantly, in vivo biodistribu-tion data in healthy mice have shown that one of the radiometalated derivatives, PepH3, crosses the BBB, accumulating in the brain, with a fast clearance from that organ and with high levels of excretion. Brought together the results have shown that this peptide vector is a very good candidate to be used has a shuttle taking cargo in and out the brain.
References: 1. L. Guo et al. Curr. Pharm. Biotechnol., 13, 2310 (2012), 2. W. M. Pardridge et al. Drug Discov. Today, 12, 54 (2007), 3. L. L. Zou et al. Curr. Neuropharmacol. 11, 197, (2013), 4. F. C. Thomas et al. Pharm. Res., 26, 2486 (2009)
Veranstalter
Kontakt
Brigitte Schwarz
Fakultät für Chemie der Universität Wien
Dekanat
01/4277-52006
brigitte_schwarz@univie.ac.at
Erstellt am Donnerstag, 05. Oktober 2017, 15:04
Letzte Änderung am Montag, 09. Oktober 2017, 09:47