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dc.contributor.author
Pastor Flores, Daniel  
dc.contributor.author
Schulze, Jörg O.  
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Bahí, Anna  
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Giacometti, Romina  
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Ferrer Dalmau, Jofre  
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Passeron, Susana  
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Engel, Matthias  
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Süß, Evelyn  
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Casamayor, Antonio  
dc.contributor.author
Biondi, Ricardo Miguel  
dc.date.available
2015-08-12T14:23:47Z  
dc.date.issued
2013-08-02  
dc.identifier.citation
Pastor Flores, Daniel; Schulze, Jörg O.; Bahí, Anna; Giacometti, Romina; Ferrer Dalmau, Jofre; et al.; PIF-Pocket as a Target for C. albicans Pkh Selective Inhibitors; American Chemical Society; ACS Chemical Biology; 8; 10; 2-8-2013; 2283-2292  
dc.identifier.issn
1554-8929  
dc.identifier.uri
http://hdl.handle.net/11336/1637  
dc.description.abstract
The phosphoinositide-dependent protein kinase 1, PDK1, is a master kinase that phosphorylates the activation loop of up to 23 AGC kinases. S. cerevisiae has three PDK1 orthologues, Pkh1 −3, which also phosphorylate AGC kinases (e.g., Ypk, Tpk, Pkc1, and Sch9). Pkh1 and 2 are redundant proteins involved in multiple essential cellular functions, including endocytosis and cell wall integrity. Based on similarities with the budding yeast, the Pkh of fungal infectious species was postulated as a novel target for antifungals. Here, we found that depletion of Pkh eventually induces o xi dat ive s tress and DNA do ubl e-strand breaks, l eading to programmed cell death. This finding supports Pkh as an antifungal target since pharmacological inhibition of Pkh would lead to the death of yeast cells, the ultimate goal of antifungals. It was therefore of interest to further investigate the possibility to develop Pkh inhibitors with selectivity for Candida Pkh that would not inhibit the human ortholog. Here, we describe C. albicans Pkh2 biochemically, structurally and by using chemical probes in comparison to human PDK1. We found that a regulatory site on the C. albicans Pkh2 catalytic domain, the PIF-pocket, diverges from human PDK1. Indeed, we identi fied and characterized PS77 , a new small allosteric inhibitor directed to the PIF-pocket, which has increased selectivity for C. albicans Pkh2. Together, our results describe novel features of the biology of Pkh and chemical biology approaches that support the validation of Pkh as a drug target for selective antifungals.  
dc.format
application/pdf  
dc.language.iso
eng  
dc.publisher
American Chemical Society  
dc.rights
info:eu-repo/semantics/openAccess  
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/  
dc.subject
Candida Albicans  
dc.subject
Pdk1  
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Pif-Pocket  
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Inhibitors  
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Bioquímica y Biología Molecular  
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Ciencias Biológicas  
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CIENCIAS NATURALES Y EXACTAS  
dc.title
PIF-Pocket as a Target for C. albicans Pkh Selective Inhibitors  
dc.type
info:eu-repo/semantics/article  
dc.type
info:ar-repo/semantics/artículo  
dc.type
info:eu-repo/semantics/publishedVersion  
dc.date.updated
2016-03-30 10:35:44.97925-03  
dc.journal.volume
8  
dc.journal.number
10  
dc.journal.pagination
2283-2292  
dc.journal.pais
Estados Unidos  
dc.journal.ciudad
Washington  
dc.description.fil
Fil: Pastor Flores, Daniel. Universitatsklinikum Frankfurt. Medizinische Klinik. Research Group PhosphoSites; Alemania;  
dc.description.fil
Fil: Schulze, Jörg O.. Universitatsklinikum Frankfurt. Medizinische Klinik. Research Group PhosphoSites; Alemania;  
dc.description.fil
Fil: Bahí, Anna. Universidad Autónoma de Barcelona. Facultad de Veterinaria. Departamento de Bioquímica y Biología Molecular; España; Universidad Autónoma de Barcelona. Instituto de Biotecnología y Biomedicina; España;  
dc.description.fil
Fil: Giacometti, Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico - CONICET - Parque Centenario. Instituto de Investigaciones en Biociencias Agrícolas y Ambientales; Argentina; Universidad de Buenos Aires. Facultad de Agronomía. Catedra de Bioquímica; Argentina;  
dc.description.fil
Fil: Ferrer Dalmau, Jofre. Universidad Autónoma de Barcelona. Facultad de Veterinaria. Departamento de Bioquímica y Biología Molecular; España; Universidad Autónoma de Barcelona. Instituto de Biotecnología y Biomedicina; España;  
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Fil: Passeron, Susana. Universidad de Buenos Aires. Facultad de Agronomia. Departamento de Biologia Aplicada y Alimentos. Cat. de Bioquimica;  
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Fil: Engel, Matthias. Universitat Saarland. Pharmaceutical and Medicinal Chemistry; Alemania;  
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Fil: Süß, Evelyn. Universitatsklinikum Frankfurt. Medizinische Klinik. Research Group PhosphoSites; Alemania;  
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Fil: Casamayor, Antonio. Universidad Autónoma de Barcelona. Facultad de Veterinaria. Departamento de Bioquímica y Biología Molecular; España; Universidad Autónoma de Barcelona. Instituto de Biotecnología y Biomedicina; España;  
dc.description.fil
Fil: Biondi, Ricardo Miguel. Goethe Universitat Frankfurt; Alemania; Universitatsklinikum Frankfurt. Medizinische Klinik. Research Group PhosphoSites; Alemania;  
dc.journal.title
ACS Chemical Biology  
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/http://pubs.acs.org/doi/abs/10.1021/cb400452z