Receptor binding mode and pharmacological characterization of a potent and selective dual CXCR1/CXCR2 non-competitive allosteric inhibitor

Autores
Bertini, R.; Barcelos, L. S.; Beccari, A. R.; Cavalieri, B.; Moriconi, A.; Bizzarri, C.; Di Benedetto, P.; Di Giacinto, C.; Gloaguen, I.; Galliera, E.; Corsi, M. M.; Russo, R. C.; Andrade, S. P.; Cesta, M. C.; Nano, G.; Aramini, A.; Cutrin, Juan Carlos; Locati, M.; Allegretti, M.; Teixeira, M. M.
Año de publicación
2012
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Background and Purpose: DF 2156A is a new dual inhibitor of IL-8 receptors CXCR1 and CXCR2 with an optimal pharmacokinetic profile. We characterized its binding mode, molecular mechanism of action and selectivity, and evaluated its therapeutic potential. Experimental Approach: The binding mode, molecular mechanism of action and selectivity were investigated using chemotaxis of L1.2 transfectants and human leucocytes, in addition to radioligand and [ 35S]-GTPγS binding approaches. The therapeutic potential of DF 2156A was evaluated in acute (liver ischaemia and reperfusion) and chronic (sponge-induced angiogenesis) experimental models of inflammation. Key Results: A network of polar interactions stabilized by a direct ionic bond between DF 2156A and Lys99 on CXCR1 and the non-conserved residue Asp 293 on CXCR2 are the key determinants of DF 2156A binding. DF 2156A acted as a non-competitive allosteric inhibitor blocking the signal transduction leading to chemotaxis without altering the binding affinity of natural ligands. DF 2156A effectively and selectively inhibited CXCR1/CXCR2-mediated chemotaxis of L1.2 transfectants and leucocytes. In a murine model of sponge-induced angiogenesis, DF 2156A reduced leucocyte influx, TNF-α production and neovessel formation. In vitro, DF 2156A prevented proliferation, migration and capillary-like organization of HUVECs in response to human IL-8. In a rat model of liver ischaemia and reperfusion (I/R) injury, DF 2156A decreased PMN and monocyte-macrophage infiltration and associated hepatocellular injury. Conclusion and Implications: DF 2156A is a non-competitive allosteric inhibitor of both IL-8 receptors CXCR1 and CXCR2. It prevented experimental angiogenesis and hepatic I/R injury in vivo and, therefore, has therapeutic potential for acute and chronic inflammatory diseases.
Fil: Bertini, R.. Dompé; Italia
Fil: Barcelos, L. S.. Universidade Federal de Minas Gerais; Brasil
Fil: Beccari, A. R.. Dompé; Italia
Fil: Cavalieri, B.. Dompé; Italia. Università di Torino; Italia
Fil: Moriconi, A.. Dompé; Italia
Fil: Bizzarri, C.. Dompé; Italia
Fil: Di Benedetto, P.. Dompé; Italia
Fil: Di Giacinto, C.. Dompé; Italia
Fil: Gloaguen, I.. Dompé; Italia
Fil: Galliera, E.. Università degli Studi di Milano; Italia
Fil: Corsi, M. M.. Università degli Studi di Milano; Italia. Policlinico San Donato IRCCS; Italia
Fil: Russo, R. C.. Universidade Federal de Minas Gerais; Brasil
Fil: Andrade, S. P.. Universidade Federal de Minas Gerais; Brasil
Fil: Cesta, M. C.. Dompé; Italia
Fil: Nano, G.. Dompé; Italia
Fil: Aramini, A.. Dompé; Italia
Fil: Cutrin, Juan Carlos. Università di Torino; Italia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Cardiológicas; Argentina
Fil: Locati, M.. Università degli Studi di Milano; Italia
Fil: Allegretti, M.. Dompé; Italia
Fil: Teixeira, M. M.. Universidade Federal de Minas Gerais; Brasil
Materia
Binding Mode
Chemokine Receptors
Cxcr1/Cxcr2
Experimental Angiogenesis
Ischaemia Reperfusion Injury
Leucocyte Recruitment
Non-Competitive Allosteric Inhibitor
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/67582
Acceder
id CONICETDig_553819158ee25536befb4cb61468d839
oai_identifier_str oai:ri.conicet.gov.ar:11336/67582
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Receptor binding mode and pharmacological characterization of a potent and selective dual CXCR1/CXCR2 non-competitive allosteric inhibitorBertini, R.Barcelos, L. S.Beccari, A. R.Cavalieri, B.Moriconi, A.Bizzarri, C.Di Benedetto, P.Di Giacinto, C.Gloaguen, I.Galliera, E.Corsi, M. M.Russo, R. C.Andrade, S. P.Cesta, M. C.Nano, G.Aramini, A.Cutrin, Juan CarlosLocati, M.Allegretti, M.Teixeira, M. M.Binding ModeChemokine ReceptorsCxcr1/Cxcr2Experimental AngiogenesisIschaemia Reperfusion InjuryLeucocyte RecruitmentNon-Competitive Allosteric Inhibitorhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Background and Purpose: DF 2156A is a new dual inhibitor of IL-8 receptors CXCR1 and CXCR2 with an optimal pharmacokinetic profile. We characterized its binding mode, molecular mechanism of action and selectivity, and evaluated its therapeutic potential. Experimental Approach: The binding mode, molecular mechanism of action and selectivity were investigated using chemotaxis of L1.2 transfectants and human leucocytes, in addition to radioligand and [ 35S]-GTPγS binding approaches. The therapeutic potential of DF 2156A was evaluated in acute (liver ischaemia and reperfusion) and chronic (sponge-induced angiogenesis) experimental models of inflammation. Key Results: A network of polar interactions stabilized by a direct ionic bond between DF 2156A and Lys99 on CXCR1 and the non-conserved residue Asp 293 on CXCR2 are the key determinants of DF 2156A binding. DF 2156A acted as a non-competitive allosteric inhibitor blocking the signal transduction leading to chemotaxis without altering the binding affinity of natural ligands. DF 2156A effectively and selectively inhibited CXCR1/CXCR2-mediated chemotaxis of L1.2 transfectants and leucocytes. In a murine model of sponge-induced angiogenesis, DF 2156A reduced leucocyte influx, TNF-α production and neovessel formation. In vitro, DF 2156A prevented proliferation, migration and capillary-like organization of HUVECs in response to human IL-8. In a rat model of liver ischaemia and reperfusion (I/R) injury, DF 2156A decreased PMN and monocyte-macrophage infiltration and associated hepatocellular injury. Conclusion and Implications: DF 2156A is a non-competitive allosteric inhibitor of both IL-8 receptors CXCR1 and CXCR2. It prevented experimental angiogenesis and hepatic I/R injury in vivo and, therefore, has therapeutic potential for acute and chronic inflammatory diseases.Fil: Bertini, R.. Dompé; ItaliaFil: Barcelos, L. S.. Universidade Federal de Minas Gerais; BrasilFil: Beccari, A. R.. Dompé; ItaliaFil: Cavalieri, B.. Dompé; Italia. Università di Torino; ItaliaFil: Moriconi, A.. Dompé; ItaliaFil: Bizzarri, C.. Dompé; ItaliaFil: Di Benedetto, P.. Dompé; ItaliaFil: Di Giacinto, C.. Dompé; ItaliaFil: Gloaguen, I.. Dompé; ItaliaFil: Galliera, E.. Università degli Studi di Milano; ItaliaFil: Corsi, M. M.. Università degli Studi di Milano; Italia. Policlinico San Donato IRCCS; ItaliaFil: Russo, R. C.. Universidade Federal de Minas Gerais; BrasilFil: Andrade, S. P.. Universidade Federal de Minas Gerais; BrasilFil: Cesta, M. C.. Dompé; ItaliaFil: Nano, G.. Dompé; ItaliaFil: Aramini, A.. Dompé; ItaliaFil: Cutrin, Juan Carlos. Università di Torino; Italia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Cardiológicas; ArgentinaFil: Locati, M.. Università degli Studi di Milano; ItaliaFil: Allegretti, M.. Dompé; ItaliaFil: Teixeira, M. M.. Universidade Federal de Minas Gerais; BrasilWiley Blackwell Publishing, Inc2012-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/67582Bertini, R.; Barcelos, L. S.; Beccari, A. R.; Cavalieri, B.; Moriconi, A.; et al.; Receptor binding mode and pharmacological characterization of a potent and selective dual CXCR1/CXCR2 non-competitive allosteric inhibitor; Wiley Blackwell Publishing, Inc; British Journal of Pharmacology; 165; 2; 1-2012; 436-4540007-1188CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1111/j.1476-5381.2011.01566.xinfo:eu-repo/semantics/altIdentifier/url/https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1111/j.1476-5381.2011.01566.xinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:09:05Zoai:ri.conicet.gov.ar:11336/67582instacron: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:34982025-09-03 10:09:05.932CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Receptor binding mode and pharmacological characterization of a potent and selective dual CXCR1/CXCR2 non-competitive allosteric inhibitor
title Receptor binding mode and pharmacological characterization of a potent and selective dual CXCR1/CXCR2 non-competitive allosteric inhibitor
spellingShingle Receptor binding mode and pharmacological characterization of a potent and selective dual CXCR1/CXCR2 non-competitive allosteric inhibitor
Bertini, R.
Binding Mode
Chemokine Receptors
Cxcr1/Cxcr2
Experimental Angiogenesis
Ischaemia Reperfusion Injury
Leucocyte Recruitment
Non-Competitive Allosteric Inhibitor
title_short Receptor binding mode and pharmacological characterization of a potent and selective dual CXCR1/CXCR2 non-competitive allosteric inhibitor
title_full Receptor binding mode and pharmacological characterization of a potent and selective dual CXCR1/CXCR2 non-competitive allosteric inhibitor
title_fullStr Receptor binding mode and pharmacological characterization of a potent and selective dual CXCR1/CXCR2 non-competitive allosteric inhibitor
title_full_unstemmed Receptor binding mode and pharmacological characterization of a potent and selective dual CXCR1/CXCR2 non-competitive allosteric inhibitor
title_sort Receptor binding mode and pharmacological characterization of a potent and selective dual CXCR1/CXCR2 non-competitive allosteric inhibitor
dc.creator.none.fl_str_mv Bertini, R.
Barcelos, L. S.
Beccari, A. R.
Cavalieri, B.
Moriconi, A.
Bizzarri, C.
Di Benedetto, P.
Di Giacinto, C.
Gloaguen, I.
Galliera, E.
Corsi, M. M.
Russo, R. C.
Andrade, S. P.
Cesta, M. C.
Nano, G.
Aramini, A.
Cutrin, Juan Carlos
Locati, M.
Allegretti, M.
Teixeira, M. M.
author Bertini, R.
author_facet Bertini, R.
Barcelos, L. S.
Beccari, A. R.
Cavalieri, B.
Moriconi, A.
Bizzarri, C.
Di Benedetto, P.
Di Giacinto, C.
Gloaguen, I.
Galliera, E.
Corsi, M. M.
Russo, R. C.
Andrade, S. P.
Cesta, M. C.
Nano, G.
Aramini, A.
Cutrin, Juan Carlos
Locati, M.
Allegretti, M.
Teixeira, M. M.
author_role author
author2 Barcelos, L. S.
Beccari, A. R.
Cavalieri, B.
Moriconi, A.
Bizzarri, C.
Di Benedetto, P.
Di Giacinto, C.
Gloaguen, I.
Galliera, E.
Corsi, M. M.
Russo, R. C.
Andrade, S. P.
Cesta, M. C.
Nano, G.
Aramini, A.
Cutrin, Juan Carlos
Locati, M.
Allegretti, M.
Teixeira, M. M.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Binding Mode
Chemokine Receptors
Cxcr1/Cxcr2
Experimental Angiogenesis
Ischaemia Reperfusion Injury
Leucocyte Recruitment
Non-Competitive Allosteric Inhibitor
topic Binding Mode
Chemokine Receptors
Cxcr1/Cxcr2
Experimental Angiogenesis
Ischaemia Reperfusion Injury
Leucocyte Recruitment
Non-Competitive Allosteric Inhibitor
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Background and Purpose: DF 2156A is a new dual inhibitor of IL-8 receptors CXCR1 and CXCR2 with an optimal pharmacokinetic profile. We characterized its binding mode, molecular mechanism of action and selectivity, and evaluated its therapeutic potential. Experimental Approach: The binding mode, molecular mechanism of action and selectivity were investigated using chemotaxis of L1.2 transfectants and human leucocytes, in addition to radioligand and [ 35S]-GTPγS binding approaches. The therapeutic potential of DF 2156A was evaluated in acute (liver ischaemia and reperfusion) and chronic (sponge-induced angiogenesis) experimental models of inflammation. Key Results: A network of polar interactions stabilized by a direct ionic bond between DF 2156A and Lys99 on CXCR1 and the non-conserved residue Asp 293 on CXCR2 are the key determinants of DF 2156A binding. DF 2156A acted as a non-competitive allosteric inhibitor blocking the signal transduction leading to chemotaxis without altering the binding affinity of natural ligands. DF 2156A effectively and selectively inhibited CXCR1/CXCR2-mediated chemotaxis of L1.2 transfectants and leucocytes. In a murine model of sponge-induced angiogenesis, DF 2156A reduced leucocyte influx, TNF-α production and neovessel formation. In vitro, DF 2156A prevented proliferation, migration and capillary-like organization of HUVECs in response to human IL-8. In a rat model of liver ischaemia and reperfusion (I/R) injury, DF 2156A decreased PMN and monocyte-macrophage infiltration and associated hepatocellular injury. Conclusion and Implications: DF 2156A is a non-competitive allosteric inhibitor of both IL-8 receptors CXCR1 and CXCR2. It prevented experimental angiogenesis and hepatic I/R injury in vivo and, therefore, has therapeutic potential for acute and chronic inflammatory diseases.
Fil: Bertini, R.. Dompé; Italia
Fil: Barcelos, L. S.. Universidade Federal de Minas Gerais; Brasil
Fil: Beccari, A. R.. Dompé; Italia
Fil: Cavalieri, B.. Dompé; Italia. Università di Torino; Italia
Fil: Moriconi, A.. Dompé; Italia
Fil: Bizzarri, C.. Dompé; Italia
Fil: Di Benedetto, P.. Dompé; Italia
Fil: Di Giacinto, C.. Dompé; Italia
Fil: Gloaguen, I.. Dompé; Italia
Fil: Galliera, E.. Università degli Studi di Milano; Italia
Fil: Corsi, M. M.. Università degli Studi di Milano; Italia. Policlinico San Donato IRCCS; Italia
Fil: Russo, R. C.. Universidade Federal de Minas Gerais; Brasil
Fil: Andrade, S. P.. Universidade Federal de Minas Gerais; Brasil
Fil: Cesta, M. C.. Dompé; Italia
Fil: Nano, G.. Dompé; Italia
Fil: Aramini, A.. Dompé; Italia
Fil: Cutrin, Juan Carlos. Università di Torino; Italia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Cardiológicas; Argentina
Fil: Locati, M.. Università degli Studi di Milano; Italia
Fil: Allegretti, M.. Dompé; Italia
Fil: Teixeira, M. M.. Universidade Federal de Minas Gerais; Brasil
description Background and Purpose: DF 2156A is a new dual inhibitor of IL-8 receptors CXCR1 and CXCR2 with an optimal pharmacokinetic profile. We characterized its binding mode, molecular mechanism of action and selectivity, and evaluated its therapeutic potential. Experimental Approach: The binding mode, molecular mechanism of action and selectivity were investigated using chemotaxis of L1.2 transfectants and human leucocytes, in addition to radioligand and [ 35S]-GTPγS binding approaches. The therapeutic potential of DF 2156A was evaluated in acute (liver ischaemia and reperfusion) and chronic (sponge-induced angiogenesis) experimental models of inflammation. Key Results: A network of polar interactions stabilized by a direct ionic bond between DF 2156A and Lys99 on CXCR1 and the non-conserved residue Asp 293 on CXCR2 are the key determinants of DF 2156A binding. DF 2156A acted as a non-competitive allosteric inhibitor blocking the signal transduction leading to chemotaxis without altering the binding affinity of natural ligands. DF 2156A effectively and selectively inhibited CXCR1/CXCR2-mediated chemotaxis of L1.2 transfectants and leucocytes. In a murine model of sponge-induced angiogenesis, DF 2156A reduced leucocyte influx, TNF-α production and neovessel formation. In vitro, DF 2156A prevented proliferation, migration and capillary-like organization of HUVECs in response to human IL-8. In a rat model of liver ischaemia and reperfusion (I/R) injury, DF 2156A decreased PMN and monocyte-macrophage infiltration and associated hepatocellular injury. Conclusion and Implications: DF 2156A is a non-competitive allosteric inhibitor of both IL-8 receptors CXCR1 and CXCR2. It prevented experimental angiogenesis and hepatic I/R injury in vivo and, therefore, has therapeutic potential for acute and chronic inflammatory diseases.
publishDate 2012
dc.date.none.fl_str_mv 2012-01
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/11336/67582
Bertini, R.; Barcelos, L. S.; Beccari, A. R.; Cavalieri, B.; Moriconi, A.; et al.; Receptor binding mode and pharmacological characterization of a potent and selective dual CXCR1/CXCR2 non-competitive allosteric inhibitor; Wiley Blackwell Publishing, Inc; British Journal of Pharmacology; 165; 2; 1-2012; 436-454
0007-1188
CONICET Digital
CONICET
url http://hdl.handle.net/11336/67582
identifier_str_mv Bertini, R.; Barcelos, L. S.; Beccari, A. R.; Cavalieri, B.; Moriconi, A.; et al.; Receptor binding mode and pharmacological characterization of a potent and selective dual CXCR1/CXCR2 non-competitive allosteric inhibitor; Wiley Blackwell Publishing, Inc; British Journal of Pharmacology; 165; 2; 1-2012; 436-454
0007-1188
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1111/j.1476-5381.2011.01566.x
info:eu-repo/semantics/altIdentifier/url/https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1111/j.1476-5381.2011.01566.x
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Wiley Blackwell Publishing, Inc
publisher.none.fl_str_mv Wiley Blackwell Publishing, Inc
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 13.13397

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