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
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/212565
Ver los metadatos del registro completo
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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 Técnicas2025-09-29T10:19:38Zoai: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:34982025-09-29 10:19:38.742CONICET 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) |
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CONICET Digital (CONICET) |
instname_str |
Consejo Nacional de Investigaciones Científicas y Técnicas |
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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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1844614169293225984 |
score |
13.070432 |