Targeting Zika virus with new brain- and placenta-crossing peptide-porphyrin conjugates
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 i...
| Authors: | ; ; ; ; ; ; ; ; ; ; ; ; ; |
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| Format: | Article |
| Status: | Published version |
| Publication date: | 2022 |
| Country: | España |
| Institution: | Universitat Pompeu Fabra |
| Repository: | Repositorio Digital de la UPF |
| OAI Identifier: | oai:repositori.upf.edu:10230/53492 |
| Online Access: | http://hdl.handle.net/10230/53492 http://dx.doi.org/10.3390/pharmaceutics14040738 |
| Access Level: | Open access |
| Keyword: | BBB shuttles Zika virus Antivirals Blood–brain barrier Blood–placental barrier Peptide-drug conjugates Porphyrins |
| _version_ | 1878730618347454464 |
|---|---|
| author | Todorovski, Toni |
| author2 | Mendonça, Diogo A. Fernandes-Siqueira, Lorena O. Cruz-Oliveira, Christine Valle, Javier Cavaco, Marco Limas, Fernanda I. V. Neves, Vera Cadima-Couto, Iris Defaus, Sira Salomé Veiga, Ana Da Poian, Andrea T. Castanho, Miguel A.R.B. Andreu Martínez, David |
| author2_role | author author author author author author author author author author author author author |
| author_browse | Andreu Martínez, David Cadima-Couto, Iris Castanho, Miguel A.R.B. Cavaco, Marco Cruz-Oliveira, Christine Da Poian, Andrea T. Defaus, Sira Fernandes-Siqueira, Lorena O. Limas, Fernanda I. V. Mendonça, Diogo A. Neves, Vera Salomé Veiga, Ana Todorovski, Toni Valle, Javier |
| author_facet | Todorovski, Toni Mendonça, Diogo A. Fernandes-Siqueira, Lorena O. Cruz-Oliveira, Christine Valle, Javier Cavaco, Marco Limas, Fernanda I. V. Neves, Vera Cadima-Couto, Iris Defaus, Sira Salomé Veiga, Ana Da Poian, Andrea T. Castanho, Miguel A.R.B. Andreu Martínez, David |
| author_role | author |
| collection | Repositorio Digital de la UPF |
| description | 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. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | ES_1ffbbd83f4b4e2dff2294a55374294ea |
| institution | Universitat Pompeu Fabra |
| instname_str | Universitat Pompeu Fabra |
| network_acronym_str | ES |
| network_name_str | España |
| oai_identifier_str | oai:repositori.upf.edu:10230/53492 |
| publishDate | 2022 |
| publishDateSort | 2022 |
| publisher | MDPI |
| publisherStr | MDPI |
| reponame_str | Repositorio Digital de la UPF |
| spelling | Targeting Zika virus with new brain- and placenta-crossing peptide-porphyrin conjugates Todorovski, Toni Mendonça, Diogo A. Fernandes-Siqueira, Lorena O. Cruz-Oliveira, Christine Valle, Javier Cavaco, Marco Limas, Fernanda I. V. Neves, Vera Cadima-Couto, Iris Defaus, Sira Salomé Veiga, Ana Da Poian, Andrea T. Castanho, Miguel A.R.B. Andreu Martínez, David BBB shuttles Zika virus Antivirals Blood–brain barrier Blood–placental barrier Peptide-drug conjugates Porphyrins 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. 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. MDPI http://hdl.handle.net/10230/53492 http://dx.doi.org/10.3390/pharmaceutics14040738 |
| spellingShingle | Targeting Zika virus with new brain- and placenta-crossing peptide-porphyrin conjugates Todorovski, Toni BBB shuttles Zika virus Antivirals Blood–brain barrier Blood–placental barrier Peptide-drug conjugates Porphyrins |
| status_str | publishedVersion |
| title | Targeting Zika virus with new brain- and placenta-crossing peptide-porphyrin conjugates |
| title_full | Targeting Zika virus with new brain- and placenta-crossing peptide-porphyrin conjugates |
| title_fullStr | Targeting Zika virus with new brain- and placenta-crossing peptide-porphyrin conjugates |
| title_full_unstemmed | Targeting Zika virus with new brain- and placenta-crossing peptide-porphyrin conjugates |
| title_short | Targeting Zika virus with new brain- and placenta-crossing peptide-porphyrin conjugates |
| title_sort | Targeting Zika virus with new brain- and placenta-crossing peptide-porphyrin conjugates |
| topic | BBB shuttles Zika virus Antivirals Blood–brain barrier Blood–placental barrier Peptide-drug conjugates Porphyrins |
| topic_facet | BBB shuttles Zika virus Antivirals Blood–brain barrier Blood–placental barrier Peptide-drug conjugates Porphyrins |
| url | http://hdl.handle.net/10230/53492 http://dx.doi.org/10.3390/pharmaceutics14040738 |