An inhibitory mechanism of action of coiled‐coil peptides against type three secretion system from enteropathogenic Escherichia coli
Human pathogenic gram‐negative bacteria, such as enteropathogenic Escherichia coli (EPEC), rely on type III secretion systems (T3SS) to translocate virulence factors directly into host cells. The coiled‐coil domains present in the structural proteins of T3SS are conformed by amphipathic alpha‐helica...
| Autores principales: | , , , , , , , , , , |
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| Formato: | info:ar-repo/semantics/artículo |
| Lenguaje: | Inglés |
| Publicado: |
Wiley
2019
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| Materias: | |
| Acceso en línea: | https://onlinelibrary.wiley.com/doi/abs/10.1002/psc.3149 http://hdl.handle.net/20.500.12123/4808 https://doi.org/10.1002/psc.3149 |
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| author | Larzabal, Mariano Baldoni, Hector A. Suvire, Fernando D. Curto, Lucrecia M. Gomez, Gabriela E. Marques Da Silva, Wanderson Giudicessi, Silvana L. Camperi, Silvia A. Delfino, Jose M. Cataldi, Angel Adrian Enriz, Daniel |
| author_browse | Baldoni, Hector A. Camperi, Silvia A. Cataldi, Angel Adrian Curto, Lucrecia M. Delfino, Jose M. Enriz, Daniel Giudicessi, Silvana L. Gomez, Gabriela E. Larzabal, Mariano Marques Da Silva, Wanderson Suvire, Fernando D. |
| author_facet | Larzabal, Mariano Baldoni, Hector A. Suvire, Fernando D. Curto, Lucrecia M. Gomez, Gabriela E. Marques Da Silva, Wanderson Giudicessi, Silvana L. Camperi, Silvia A. Delfino, Jose M. Cataldi, Angel Adrian Enriz, Daniel |
| author_sort | Larzabal, Mariano |
| collection | INTA Digital |
| description | Human pathogenic gram‐negative bacteria, such as enteropathogenic Escherichia coli (EPEC), rely on type III secretion systems (T3SS) to translocate virulence factors directly into host cells. The coiled‐coil domains present in the structural proteins of T3SS are conformed by amphipathic alpha‐helical structures that play an important role in the protein‐protein interaction and are essential for the assembly of the translocation complex. To investigate the inhibitory capacity of these domains on the T3SS of EPEC, we synthesized peptides between 7 and 34 amino acids based on the coiled‐coil domains of proteins that make up this secretion system. This analysis was performed through in vitro hemolysis assays by assessing the reduction of T3SS‐dependent red blood cell lysis in the presence of the synthesized peptides. After confirming its inhibitory capacity, we performed molecular modeling assays using combined techniques, docking‐molecular dynamic simulations, and quantum‐mechanic calculations of the various peptide‐protein complexes, to improve the affinity of the peptides to the target proteins selected from T3SS. These techniques allowed us to demonstrate that the peptides with greater inhibitory activity, directed against the coiled‐coil domain of the C‐terminal region of EspA, present favorable hydrophobic and hydrogen bond molecular interactions. Particularly, the hydrogen bond component is responsible for the stabilization of the peptide‐protein complex. This study demonstrates that compounds targeting T3SS from pathogenic bacteria can indeed inhibit bacterial infection by presenting a higher specificity than broad‐spectrum antibiotics. In turn, these peptides could be taken as initial structures to design and synthesize new compounds that mimic their inhibitory pharmacophoric pattern. |
| format | info:ar-repo/semantics/artículo |
| id | INTA4808 |
| institution | Instituto Nacional de Tecnología Agropecuaria (INTA -Argentina) |
| language | Inglés |
| publishDate | 2019 |
| publishDateRange | 2019 |
| publishDateSort | 2019 |
| publisher | Wiley |
| publisherStr | Wiley |
| record_format | dspace |
| spelling | INTA48082019-04-03T17:13:18Z An inhibitory mechanism of action of coiled‐coil peptides against type three secretion system from enteropathogenic Escherichia coli Larzabal, Mariano Baldoni, Hector A. Suvire, Fernando D. Curto, Lucrecia M. Gomez, Gabriela E. Marques Da Silva, Wanderson Giudicessi, Silvana L. Camperi, Silvia A. Delfino, Jose M. Cataldi, Angel Adrian Enriz, Daniel Pathogenic Viruses Peptides Virus Patógenos Escherichia coli Péptidos Human pathogenic gram‐negative bacteria, such as enteropathogenic Escherichia coli (EPEC), rely on type III secretion systems (T3SS) to translocate virulence factors directly into host cells. The coiled‐coil domains present in the structural proteins of T3SS are conformed by amphipathic alpha‐helical structures that play an important role in the protein‐protein interaction and are essential for the assembly of the translocation complex. To investigate the inhibitory capacity of these domains on the T3SS of EPEC, we synthesized peptides between 7 and 34 amino acids based on the coiled‐coil domains of proteins that make up this secretion system. This analysis was performed through in vitro hemolysis assays by assessing the reduction of T3SS‐dependent red blood cell lysis in the presence of the synthesized peptides. After confirming its inhibitory capacity, we performed molecular modeling assays using combined techniques, docking‐molecular dynamic simulations, and quantum‐mechanic calculations of the various peptide‐protein complexes, to improve the affinity of the peptides to the target proteins selected from T3SS. These techniques allowed us to demonstrate that the peptides with greater inhibitory activity, directed against the coiled‐coil domain of the C‐terminal region of EspA, present favorable hydrophobic and hydrogen bond molecular interactions. Particularly, the hydrogen bond component is responsible for the stabilization of the peptide‐protein complex. This study demonstrates that compounds targeting T3SS from pathogenic bacteria can indeed inhibit bacterial infection by presenting a higher specificity than broad‐spectrum antibiotics. In turn, these peptides could be taken as initial structures to design and synthesize new compounds that mimic their inhibitory pharmacophoric pattern. Instituto de Biotecnología Fil: Larzabal, Mariano.Instituto Nacional de Tecnología Agropecuaria (INTA). UEDD IABIMO. Instituto de Agrobiotecnología y Biología Molecular. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Baldoni, Hector A. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto de Matemática Aplicada San Luis; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Suvire, Fernando D. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto Multidisciplinario de Investigaciones Biológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Curto, Lucrecia M. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Gomez, Gabriela E. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Marques Da Silva, Wanderson. Instituto Nacional de Tecnología Agropecuaria (INTA). UEDD IABIMO. Instituto de Agrobiotecnología y Biología Molecular. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Giudicessi, Silvana L. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Cátedra de Biotecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Camperi, Silvia A. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Cátedra de Biotecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Delfino, Jose M. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Cataldi, Angel Adrian. Instituto Nacional de Tecnología Agropecuaria (INTA). UEDD IABIMO. Instituto de Agrobiotecnología y Biología Molecular. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Enriz, Daniel. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto Multidisciplinario de Investigaciones Biológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina 2019-04-03T17:07:26Z 2019-04-03T17:07:26Z 2019-03 info:ar-repo/semantics/artículo info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion https://onlinelibrary.wiley.com/doi/abs/10.1002/psc.3149 http://hdl.handle.net/20.500.12123/4808 1099-1387 https://doi.org/10.1002/psc.3149 eng info:eu-repo/semantics/restrictedAccess application/pdf Wiley Journal of Peptide Science 25 (3) : e3149 (Marzo 2019) |
| spellingShingle | Pathogenic Viruses Peptides Virus Patógenos Escherichia coli Péptidos Larzabal, Mariano Baldoni, Hector A. Suvire, Fernando D. Curto, Lucrecia M. Gomez, Gabriela E. Marques Da Silva, Wanderson Giudicessi, Silvana L. Camperi, Silvia A. Delfino, Jose M. Cataldi, Angel Adrian Enriz, Daniel An inhibitory mechanism of action of coiled‐coil peptides against type three secretion system from enteropathogenic Escherichia coli |
| title | An inhibitory mechanism of action of coiled‐coil peptides against type three secretion system from enteropathogenic Escherichia coli |
| title_full | An inhibitory mechanism of action of coiled‐coil peptides against type three secretion system from enteropathogenic Escherichia coli |
| title_fullStr | An inhibitory mechanism of action of coiled‐coil peptides against type three secretion system from enteropathogenic Escherichia coli |
| title_full_unstemmed | An inhibitory mechanism of action of coiled‐coil peptides against type three secretion system from enteropathogenic Escherichia coli |
| title_short | An inhibitory mechanism of action of coiled‐coil peptides against type three secretion system from enteropathogenic Escherichia coli |
| title_sort | inhibitory mechanism of action of coiled coil peptides against type three secretion system from enteropathogenic escherichia coli |
| topic | Pathogenic Viruses Peptides Virus Patógenos Escherichia coli Péptidos |
| url | https://onlinelibrary.wiley.com/doi/abs/10.1002/psc.3149 http://hdl.handle.net/20.500.12123/4808 https://doi.org/10.1002/psc.3149 |
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