End-on PEGylation of heparin: Effect on anticoagulant activity and complexation with protamine

Detalhes bibliográficos
Autor(a) principal: Amaral, S.
Data de Publicação: 2023
Outros Autores: Lozano-Fernández, T., Sabin, J., Gallego, A., da Silva Morais, Alain, Reis, R. L., Gonzalez-Fernández, A., Pashkuleva, I., Novoa-Carballal, Ramon
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: https://hdl.handle.net/1822/85961
Resumo: Supplementary data to this article can be found online at https://doi.org/10.1016/j.ijbiomac.2023.125957.
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spelling End-on PEGylation of heparin: Effect on anticoagulant activity and complexation with protamineAntithrombinGlycosaminoglycanisothermal calorimetryoxime ligationProtamineReducing endSupplementary data to this article can be found online at https://doi.org/10.1016/j.ijbiomac.2023.125957.Heparin is the most common anticoagulant used in clinical practice but shows some downsides such as short half- life (for the high molecular weight heparin) and secondary effects. On the other hand, its low molecular weight analogue cannot be neutralized with protamine, and therefore cannot be used in some treatments. To address these issues, we conjugated polyethylene glycol (PEG) to heparin reducing end (end-on) via oxime ligation and studied the interactions of the conjugate (Hep-b-PEG) with antithrombin III (AT) and protamine. Isothermal titration calorimetry showed that Hep-b-PEG maintains the affinity to AT. Dynamic light scattering demonstrated that the Hep-b-PEG formed colloidal stable nanocomplexes with protamine instead of large multi-molecular aggregates, associated with heparin side effects. The in vitro (human plasma) and in vivo experiments (Sprague Dawley rats) evidenced an extended half-life and higher anticoagulant activity of the conjugate when compared to unmodified heparin.  The authors thank INNO Laboratório Veterinário for the measurements of in vivo coagulation times, Raul Pacheco for discussions about the ITC results, Teresa Oliveira for her help in the in vivo experiments and Ramón Rail for his help in the 3D structures of Fig. 1, Fig. 4. We thank funding provided by the Portuguese Foundation for Science and Technology (PTDC/QUI-POL/28117/2017 and CEECIND/00814/2017). África González-Fernández thanks Xunta de Galicia (Grupo de Referencia competitiva, GRC-ED431C 2020/02) 2020-2023.ElsevierUniversidade do MinhoAmaral, S.Lozano-Fernández, T.Sabin, J.Gallego, A.da Silva Morais, AlainReis, R. L.Gonzalez-Fernández, A.Pashkuleva, I.Novoa-Carballal, Ramon2023-072023-07-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/1822/85961engAmaral, S., Lozano-Fernández, T., Sabin, J., Gallego, A., da Silva Morais, A., Reis, R. L., … Novoa-Carballal, R. (2023, September). End-on PEGylation of heparin: Effect on anticoagulant activity and complexation with protamine. International Journal of Biological Macromolecules. Elsevier BV. http://doi.org/10.1016/j.ijbiomac.2023.1259570141-813010.1016/j.ijbiomac.2023.12595737499705https://doi.org/10.1016/j.ijbiomac.2023.125957info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-08-12T01:18:02ZPortal AgregadorONG
dc.title.none.fl_str_mv End-on PEGylation of heparin: Effect on anticoagulant activity and complexation with protamine
title End-on PEGylation of heparin: Effect on anticoagulant activity and complexation with protamine
spellingShingle End-on PEGylation of heparin: Effect on anticoagulant activity and complexation with protamine
Amaral, S.
Antithrombin
Glycosaminoglycan
isothermal calorimetry
oxime ligation
Protamine
Reducing end
title_short End-on PEGylation of heparin: Effect on anticoagulant activity and complexation with protamine
title_full End-on PEGylation of heparin: Effect on anticoagulant activity and complexation with protamine
title_fullStr End-on PEGylation of heparin: Effect on anticoagulant activity and complexation with protamine
title_full_unstemmed End-on PEGylation of heparin: Effect on anticoagulant activity and complexation with protamine
title_sort End-on PEGylation of heparin: Effect on anticoagulant activity and complexation with protamine
author Amaral, S.
author_facet Amaral, S.
Lozano-Fernández, T.
Sabin, J.
Gallego, A.
da Silva Morais, Alain
Reis, R. L.
Gonzalez-Fernández, A.
Pashkuleva, I.
Novoa-Carballal, Ramon
author_role author
author2 Lozano-Fernández, T.
Sabin, J.
Gallego, A.
da Silva Morais, Alain
Reis, R. L.
Gonzalez-Fernández, A.
Pashkuleva, I.
Novoa-Carballal, Ramon
author2_role author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universidade do Minho
dc.contributor.author.fl_str_mv Amaral, S.
Lozano-Fernández, T.
Sabin, J.
Gallego, A.
da Silva Morais, Alain
Reis, R. L.
Gonzalez-Fernández, A.
Pashkuleva, I.
Novoa-Carballal, Ramon
dc.subject.por.fl_str_mv Antithrombin
Glycosaminoglycan
isothermal calorimetry
oxime ligation
Protamine
Reducing end
topic Antithrombin
Glycosaminoglycan
isothermal calorimetry
oxime ligation
Protamine
Reducing end
description Supplementary data to this article can be found online at https://doi.org/10.1016/j.ijbiomac.2023.125957.
publishDate 2023
dc.date.none.fl_str_mv 2023-07
2023-07-01T00:00:00Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv https://hdl.handle.net/1822/85961
url https://hdl.handle.net/1822/85961
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv Amaral, S., Lozano-Fernández, T., Sabin, J., Gallego, A., da Silva Morais, A., Reis, R. L., … Novoa-Carballal, R. (2023, September). End-on PEGylation of heparin: Effect on anticoagulant activity and complexation with protamine. International Journal of Biological Macromolecules. Elsevier BV. http://doi.org/10.1016/j.ijbiomac.2023.125957
0141-8130
10.1016/j.ijbiomac.2023.125957
37499705
https://doi.org/10.1016/j.ijbiomac.2023.125957
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron:RCAAP
instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron_str RCAAP
institution RCAAP
reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv
repository.mail.fl_str_mv
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