Targeting Zika virus with new brain- and placenta-crossing peptide-porphyrin conjugates

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• dc.contributor.author Todorovski, Toni
• dc.contributor.author Mendonça, Diogo A.
• dc.contributor.author Fernandes-Siqueira, Lorena O.
• dc.contributor.author Cruz-Oliveira, Christine
• dc.contributor.author Valle, Javier
• dc.contributor.author Cavaco, Marco
• dc.contributor.author Limas, Fernanda I. V.
• dc.contributor.author Neves, Vera
• dc.contributor.author Cadima-Couto, Iris
• dc.contributor.author Defaus, Sira
• dc.contributor.author Salomé Veiga, Ana
• dc.contributor.author Da Poian, Andrea T.
• dc.contributor.author Castanho, Miguel A.R.B.
• dc.contributor.author Andreu Martínez, David
• dc.date.accessioned 2022-06-15T06:28:58Z
• dc.date.available 2022-06-15T06:28:58Z
• dc.date.issued 2022
• dc.description.abstract Viral disease outbreaks affect hundreds of millions of people worldwide and remain a serious threat to global health. The current SARS-CoV-2 pandemic and other recent geographically- confined viral outbreaks (severe acute respiratory syndrome (SARS), Ebola, dengue, zika and ever-recurring seasonal influenza), also with devastating tolls at sanitary and socio-economic levels, are sobering reminders in this respect. Among the respective pathogenic agents, Zika virus (ZIKV), transmitted by Aedes mosquito vectors and causing the eponymous fever, is particularly insidious in that infection during pregnancy results in complications such as foetal loss, preterm birth or irreversible brain abnormalities, including microcephaly. So far, there is no effective remedy for ZIKV infection, mainly due to the limited ability of antiviral drugs to cross blood-placental and/or blood-brain barriers (BPB and BBB, respectively). Despite its restricted permeability, the BBB is penetrable by a variety of molecules, mainly peptide-based, and named BBB peptide shuttles (BBBpS), able to ferry various payloads (e.g., drugs, antibodies, etc.) into the brain. Recently, we have described peptide-porphyrin conjugates (PPCs) as successful BBBpS-associated drug leads for HIV, an enveloped virus in which group ZIKV also belongs. Herein, we report on several brain-directed, low-toxicity PPCs capable of targeting ZIKV. One of the conjugates, PP-P1, crossing both BPB and BBB, has shown to be effective against ZIKV (IC50 1.08 µM) and has high serum stability (t1/2 ca. 22 h) without altering cell viability at all tested concentrations. Peptide-porphyrin conjugation stands out as a promising strategy to fill the ZIKV treatment gap.
• dc.description.sponsorship Work supported by the La Caixa Health Foundation (project HR17_00409, ID 100010434, agreement LCF/PR/HR17/52150011) and by the European Union (H2020-FETOPEN-2018-2019-2020-01 grant no 828774). The Department of Medicine and Life Sciences, Pompeu Fabra University, belongs to the María de Maeztu network of Units of Excellence, funded by the Spanish MICINN and AEI (CEX2018-000792-M). Additional funding from Fundação para a Ciéncia e Tecnologia (FCT-MCTES) is also acknowledged for D.A.M. (PD/BD/136752/2018), M.C. (PD/BD/128281/2017), and for C.C.-O. and Í.C.-C. (PTDC/BIAVIR/29495/2017). The grants from Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), Brazil (grant numbers 201.316/2016, 202.945/2017); and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brazil (grant number 309028/2017-5) are also acknowledged.
• dc.format.mimetype application/pdf
• dc.identifier.citation Todorovski T, Mendonça DA, Fernandes-Siqueira LO, Cruz-Oliveira C, Guida G, Valle J, Cavaco M, Limas FIV, Neves V, Cadima-Couto Í, Defaus S, Veiga AS, Da Poian AT, Castanho MARB, Andreu D. Targeting Zika virus with new brain- and placenta-crossing peptide-porphyrin conjugates. Pharmaceutics. 2022 Mar 29;14(4):738. DOI: 10.3390/pharmaceutics14040738
• dc.identifier.doi http://dx.doi.org/10.3390/pharmaceutics14040738
• dc.identifier.issn 1999-4923
• dc.identifier.uri http://hdl.handle.net/10230/53492
• dc.language.iso eng
• dc.publisher MDPI
• dc.relation.ispartof Pharmaceutics. 2022 Mar 29;14(4):738
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/828774
• dc.rights © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri https://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword BBB shuttles
• dc.subject.keyword Zika virus
• dc.subject.keyword Antivirals
• dc.subject.keyword Blood–brain barrier
• dc.subject.keyword Blood–placental barrier
• dc.subject.keyword Peptide-drug conjugates
• dc.subject.keyword Porphyrins
• dc.title Targeting Zika virus with new brain- and placenta-crossing peptide-porphyrin conjugates
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion