Pl1 peptide engages acidic surfaces on tumor-associated fibronectin and tenascin isoforms to trigger cellular uptake

Autores
Lingasamy, Prakash; Põnograjeva, Kristina; Kopanchuk, Sergei; Tobi, Allan; Rinken, Ago; General, Ignacio; Asciutto, Eliana Karina; Teesalu, Tambet
Año de publicación
2021
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Tumor extracellular matrix (ECM) is a high-capacity target for the precision delivery of affinity ligand-guided drugs and imaging agents. Recently, we developed a PL1 peptide (sequence: PPRRGLIKLKTS) for systemic targeting of malignant ECM. Here, we map the dynamics of PL1 binding to its receptors Fibronectin Extra Domain B (FN-EDB) and Tenascin C C-isoform (TNC-C) by computational modeling and cell-free binding studies on mutated receptor proteins, and study cellular binding and internalization of PL1 nanoparticles in cultured cells. Molecular dynamics simulation and docking analysis suggested that the engagement of PL1 peptide with both receptors is primarily driven by electrostatic interactions. Substituting acidic amino acid residues with neutral amino acids at predicted PL1 binding sites in FN-EDB (D52N-D49N-D12N) and TNC-C (D39N-D45N) resulted in the loss of binding of PL1 nanoparticles. Remarkably, PL1-functionalized nanoparticles (NPs) were not only deposited on the target ECM but bound the cells and initiated a robust cellular uptake via a pathway resembling macropinocytosis. Our studies establish the mode of engagement of the PL1 peptide with its receptors and suggest applications for intracellular delivery of nanoscale payloads. The outcomes of this work can be used for the development of PL1-derived peptides with improved stability, affinity, and specificity for precision targeting of the tumor ECM and malignant cells.
Fil: Lingasamy, Prakash. University of Tartu; Estonia
Fil: Põnograjeva, Kristina. University of Tartu; Estonia
Fil: Kopanchuk, Sergei. University of Tartu; Estonia
Fil: Tobi, Allan. University of Tartu; Estonia
Fil: Rinken, Ago. University of Tartu; Estonia
Fil: General, Ignacio. University of California; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Asciutto, Eliana Karina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Ciencias Físicas. - Universidad Nacional de San Martín. Instituto de Ciencias Físicas; Argentina
Fil: Teesalu, Tambet. University of Tartu; Estonia
Materia
EXTRACELLULAR MATRIX (ECM)
FIBRONECTIN
GLIOBLASTOMA
MOLECULAR DOCKING
MOLECULAR DYNAMICS SIMULATIONS
NANOPARTICLES
TENASCIN-C
TUMOR HOMING PEPTIDE
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/212565
Acceder
id CONICETDig_06b609ae281868f627e5fca61e45500c
oai_identifier_str oai:ri.conicet.gov.ar:11336/212565
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Pl1 peptide engages acidic surfaces on tumor-associated fibronectin and tenascin isoforms to trigger cellular uptakeLingasamy, PrakashPõnograjeva, KristinaKopanchuk, SergeiTobi, AllanRinken, AgoGeneral, IgnacioAsciutto, Eliana KarinaTeesalu, TambetEXTRACELLULAR MATRIX (ECM)FIBRONECTINGLIOBLASTOMAMOLECULAR DOCKINGMOLECULAR DYNAMICS SIMULATIONSNANOPARTICLESTENASCIN-CTUMOR HOMING PEPTIDEhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1https://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Tumor extracellular matrix (ECM) is a high-capacity target for the precision delivery of affinity ligand-guided drugs and imaging agents. Recently, we developed a PL1 peptide (sequence: PPRRGLIKLKTS) for systemic targeting of malignant ECM. Here, we map the dynamics of PL1 binding to its receptors Fibronectin Extra Domain B (FN-EDB) and Tenascin C C-isoform (TNC-C) by computational modeling and cell-free binding studies on mutated receptor proteins, and study cellular binding and internalization of PL1 nanoparticles in cultured cells. Molecular dynamics simulation and docking analysis suggested that the engagement of PL1 peptide with both receptors is primarily driven by electrostatic interactions. Substituting acidic amino acid residues with neutral amino acids at predicted PL1 binding sites in FN-EDB (D52N-D49N-D12N) and TNC-C (D39N-D45N) resulted in the loss of binding of PL1 nanoparticles. Remarkably, PL1-functionalized nanoparticles (NPs) were not only deposited on the target ECM but bound the cells and initiated a robust cellular uptake via a pathway resembling macropinocytosis. Our studies establish the mode of engagement of the PL1 peptide with its receptors and suggest applications for intracellular delivery of nanoscale payloads. The outcomes of this work can be used for the development of PL1-derived peptides with improved stability, affinity, and specificity for precision targeting of the tumor ECM and malignant cells.Fil: Lingasamy, Prakash. University of Tartu; EstoniaFil: Põnograjeva, Kristina. University of Tartu; EstoniaFil: Kopanchuk, Sergei. University of Tartu; EstoniaFil: Tobi, Allan. University of Tartu; EstoniaFil: Rinken, Ago. University of Tartu; EstoniaFil: General, Ignacio. University of California; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Asciutto, Eliana Karina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Ciencias Físicas. - Universidad Nacional de San Martín. Instituto de Ciencias Físicas; ArgentinaFil: Teesalu, Tambet. University of Tartu; EstoniaMDPI2021-12info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/212565Lingasamy, Prakash; Põnograjeva, Kristina; Kopanchuk, Sergei; Tobi, Allan; Rinken, Ago; et al.; Pl1 peptide engages acidic surfaces on tumor-associated fibronectin and tenascin isoforms to trigger cellular uptake; MDPI; Pharmaceutics; 13; 12; 12-2021; 1-141999-4923CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.mdpi.com/1999-4923/13/12/1998info:eu-repo/semantics/altIdentifier/doi/10.3390/pharmaceutics13121998info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:52:18Zoai:ri.conicet.gov.ar:11336/212565instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-22 11:52:18.745CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Pl1 peptide engages acidic surfaces on tumor-associated fibronectin and tenascin isoforms to trigger cellular uptake
title Pl1 peptide engages acidic surfaces on tumor-associated fibronectin and tenascin isoforms to trigger cellular uptake
spellingShingle Pl1 peptide engages acidic surfaces on tumor-associated fibronectin and tenascin isoforms to trigger cellular uptake
Lingasamy, Prakash
EXTRACELLULAR MATRIX (ECM)
FIBRONECTIN
GLIOBLASTOMA
MOLECULAR DOCKING
MOLECULAR DYNAMICS SIMULATIONS
NANOPARTICLES
TENASCIN-C
TUMOR HOMING PEPTIDE
title_short Pl1 peptide engages acidic surfaces on tumor-associated fibronectin and tenascin isoforms to trigger cellular uptake
title_full Pl1 peptide engages acidic surfaces on tumor-associated fibronectin and tenascin isoforms to trigger cellular uptake
title_fullStr Pl1 peptide engages acidic surfaces on tumor-associated fibronectin and tenascin isoforms to trigger cellular uptake
title_full_unstemmed Pl1 peptide engages acidic surfaces on tumor-associated fibronectin and tenascin isoforms to trigger cellular uptake
title_sort Pl1 peptide engages acidic surfaces on tumor-associated fibronectin and tenascin isoforms to trigger cellular uptake
dc.creator.none.fl_str_mv Lingasamy, Prakash
Põnograjeva, Kristina
Kopanchuk, Sergei
Tobi, Allan
Rinken, Ago
General, Ignacio
Asciutto, Eliana Karina
Teesalu, Tambet
author Lingasamy, Prakash
author_facet Lingasamy, Prakash
Põnograjeva, Kristina
Kopanchuk, Sergei
Tobi, Allan
Rinken, Ago
General, Ignacio
Asciutto, Eliana Karina
Teesalu, Tambet
author_role author
author2 Põnograjeva, Kristina
Kopanchuk, Sergei
Tobi, Allan
Rinken, Ago
General, Ignacio
Asciutto, Eliana Karina
Teesalu, Tambet
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv EXTRACELLULAR MATRIX (ECM)
FIBRONECTIN
GLIOBLASTOMA
MOLECULAR DOCKING
MOLECULAR DYNAMICS SIMULATIONS
NANOPARTICLES
TENASCIN-C
TUMOR HOMING PEPTIDE
topic EXTRACELLULAR MATRIX (ECM)
FIBRONECTIN
GLIOBLASTOMA
MOLECULAR DOCKING
MOLECULAR DYNAMICS SIMULATIONS
NANOPARTICLES
TENASCIN-C
TUMOR HOMING PEPTIDE
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Tumor extracellular matrix (ECM) is a high-capacity target for the precision delivery of affinity ligand-guided drugs and imaging agents. Recently, we developed a PL1 peptide (sequence: PPRRGLIKLKTS) for systemic targeting of malignant ECM. Here, we map the dynamics of PL1 binding to its receptors Fibronectin Extra Domain B (FN-EDB) and Tenascin C C-isoform (TNC-C) by computational modeling and cell-free binding studies on mutated receptor proteins, and study cellular binding and internalization of PL1 nanoparticles in cultured cells. Molecular dynamics simulation and docking analysis suggested that the engagement of PL1 peptide with both receptors is primarily driven by electrostatic interactions. Substituting acidic amino acid residues with neutral amino acids at predicted PL1 binding sites in FN-EDB (D52N-D49N-D12N) and TNC-C (D39N-D45N) resulted in the loss of binding of PL1 nanoparticles. Remarkably, PL1-functionalized nanoparticles (NPs) were not only deposited on the target ECM but bound the cells and initiated a robust cellular uptake via a pathway resembling macropinocytosis. Our studies establish the mode of engagement of the PL1 peptide with its receptors and suggest applications for intracellular delivery of nanoscale payloads. The outcomes of this work can be used for the development of PL1-derived peptides with improved stability, affinity, and specificity for precision targeting of the tumor ECM and malignant cells.
Fil: Lingasamy, Prakash. University of Tartu; Estonia
Fil: Põnograjeva, Kristina. University of Tartu; Estonia
Fil: Kopanchuk, Sergei. University of Tartu; Estonia
Fil: Tobi, Allan. University of Tartu; Estonia
Fil: Rinken, Ago. University of Tartu; Estonia
Fil: General, Ignacio. University of California; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Asciutto, Eliana Karina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Ciencias Físicas. - Universidad Nacional de San Martín. Instituto de Ciencias Físicas; Argentina
Fil: Teesalu, Tambet. University of Tartu; Estonia
description Tumor extracellular matrix (ECM) is a high-capacity target for the precision delivery of affinity ligand-guided drugs and imaging agents. Recently, we developed a PL1 peptide (sequence: PPRRGLIKLKTS) for systemic targeting of malignant ECM. Here, we map the dynamics of PL1 binding to its receptors Fibronectin Extra Domain B (FN-EDB) and Tenascin C C-isoform (TNC-C) by computational modeling and cell-free binding studies on mutated receptor proteins, and study cellular binding and internalization of PL1 nanoparticles in cultured cells. Molecular dynamics simulation and docking analysis suggested that the engagement of PL1 peptide with both receptors is primarily driven by electrostatic interactions. Substituting acidic amino acid residues with neutral amino acids at predicted PL1 binding sites in FN-EDB (D52N-D49N-D12N) and TNC-C (D39N-D45N) resulted in the loss of binding of PL1 nanoparticles. Remarkably, PL1-functionalized nanoparticles (NPs) were not only deposited on the target ECM but bound the cells and initiated a robust cellular uptake via a pathway resembling macropinocytosis. Our studies establish the mode of engagement of the PL1 peptide with its receptors and suggest applications for intracellular delivery of nanoscale payloads. The outcomes of this work can be used for the development of PL1-derived peptides with improved stability, affinity, and specificity for precision targeting of the tumor ECM and malignant cells.
publishDate 2021
dc.date.none.fl_str_mv 2021-12
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/212565
Lingasamy, Prakash; Põnograjeva, Kristina; Kopanchuk, Sergei; Tobi, Allan; Rinken, Ago; et al.; Pl1 peptide engages acidic surfaces on tumor-associated fibronectin and tenascin isoforms to trigger cellular uptake; MDPI; Pharmaceutics; 13; 12; 12-2021; 1-14
1999-4923
CONICET Digital
CONICET
url http://hdl.handle.net/11336/212565
identifier_str_mv Lingasamy, Prakash; Põnograjeva, Kristina; Kopanchuk, Sergei; Tobi, Allan; Rinken, Ago; et al.; Pl1 peptide engages acidic surfaces on tumor-associated fibronectin and tenascin isoforms to trigger cellular uptake; MDPI; Pharmaceutics; 13; 12; 12-2021; 1-14
1999-4923
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.mdpi.com/1999-4923/13/12/1998
info:eu-repo/semantics/altIdentifier/doi/10.3390/pharmaceutics13121998
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 12.982451

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