University of Lisbon, Portugal
Developing Broad Spectrum Brain-Targeting Peptide-Drug Conjugates Against Flaviviruses and Other Envelope Viruses
SESSION 6: PEPTIDE DRUG DISCOVERY
Monday, June 26, 2023, at 02:55 pm - 03:20 pm
We are developing drugs able to inactivate Zika virus, Dengue virus, HIV, and SARS-CoV-2, among others, while having the ability to traverse the blood-brain and blood-placenta barriers, BBB and BPB, respectively. Zika is of particular interest because it combines high pandemic potential with severe neurological impairment in newborns when the infection takes place in pregnant women. So far, there is no effective therapy for infection with this virus due to the limited ability of current antiviral drugs to cross the BBB and/or the BPB.
Chemically, the drugs underdevelopment consist on the conjugation of an antiviral porphyrin to a trans-BBB carrier peptide. Proprietary trans-BBB peptides were obtained from templates based on domains of the capsid protein of Dengue virus.
The activity, toxicology, and brain-targeting efficacy of a panel of conjugates were evaluated both in vitro and in vivo. One of the conjugates is able to perform transcytosis across both the BPB and the BBB, has shown to be effective against Zika Virus, IC50 1.08 µM, and has high serum stability, t1/2 ca. 22 h, without altering cell viability at all tested concentrations. In vivo tests in animals confirm their high druggability.
1. Diogo A. Mendonça, Mariët Bakker, Christine Cruz-Oliveira, Vera Neves, Maria Angeles Jiménez, Sira Defaus, Marco Cavaco, Ana Salomé Veiga, Iris Cadima-Couto, Miguel A. R. B. Castanho, David Andreu, and Toni Todorovski. Penetrating the Blood-Brain Barrier with New Peptide–Porphyrin Conjugates Having anti-HIV Activity. Bioconjugate Chem., 2021, 32, 6, 1067–1077.
Toni Todorovski, Diogo A. Mendonça, Lorena O. Fernandes-Siqueira, Christine Cruz-Oliveira, Giuseppina Guida, Javier Valle, Marco Cavaco, Fernanda I. V. Limas, Vera Neves, Íris Cadima-Couto, Sira Defaus, Ana Salomé Veiga, Andrea T. Da Poian, Miguel A. R. B. Castanho, and David Andreu. Targeting Zika Virus with New Brain- and Placenta-Crossing Peptide–Porphyrin Conjugates. Pharmaceutics, 2022, 14(4), 738.
This work is supported by the European Union, H2020-FETOPEN-2018-2019-2020-01 grant no 828774.
Our goal is to unravel the physical principles that govern interactions at the molecular level of several clinically relevant compounds with model cell systems, with the objectives of developing new drugs and better understand the mechanism of action of already established ones.