Synthetic Conjugates of Ursodeoxycholic Acid Inhibit Cystogenesis in Experimental Models of Polycystic Liver Disease
Caballero-Camino, F. J. (Hospital Universitario de Donostia (Sant Sebastià, País Basc))
Rivilla, I. (Department of Organic Chemistry I. Center of Innovation in Advanced Chemistry (ORFEO-CINQA). University of the Basque Country/Euskal Herriko Unibertsitatea (UPV/EHU). Donostia International Physics Center (DIPC))
Herraez, Elisa (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas)
Briz, O. (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas)
Santos-Laso, A. (Hospital Universitario de Donostia (Sant Sebastià, País Basc))
Izquierdo-Sanchez, Laura (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas)
Lee-Law, P. Y. (Hospital Universitario de Donostia (Sant Sebastià, País Basc))
Rodrigues, P. M. (Hospital Universitario de Donostia (Sant Sebastià, País Basc))
Munoz-Garrido, P. (Hospital Universitario de Donostia (Sant Sebastià, País Basc))
Jin, S. (Masonic Cancer Center. University of Minnesota)
Peixoto, E. (Masonic Cancer Center. University of Minnesota)
Richard, S. (Masonic Cancer Center. University of Minnesota)
Gradilone, S. A. (Masonic Cancer Center. University of Minnesota)
Perugorria, M. J. (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas)
Esteller, M. (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Bujanda, Luis (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas)
Marin, J. J. G. (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas)
Banales, Jesus (IKERBASQUE. Basque Foundation for Science)
Cossío, Fernando P (Department of Organic Chemistry I. Center of Innovation in Advanced Chemistry (ORFEO-CINQA). University of the Basque Country/Euskal Herriko Unibertsitatea (UPV/EHU). Donostia International Physics Center (DIPC))
Universitat Autònoma de Barcelona

Date:	2020
Abstract:	Background and Aims: Polycystic liver diseases (PLDs) are genetic disorders characterized by progressive development of symptomatic biliary cysts. Current surgical and pharmacological approaches are ineffective, and liver transplantation represents the only curative option. Ursodeoxycholic acid (UDCA) and histone deacetylase 6 inhibitors (HDAC6is) have arisen as promising therapeutic strategies, but with partial benefits. Approach and Results: Here, we tested an approach based on the design, synthesis, and validation of a family of UDCA synthetic conjugates with selective HDAC6i capacity (UDCA-HDAC6i). Four UDCA-HDAC6i conjugates presented selective HDAC6i activity, UDCA-HDAC6i #1 being the most promising candidate. UDCA orientation within the UDCA-HDAC6i structure was determinant for HDAC6i activity and selectivity. Treatment of polycystic rats with UDCA-HDAC6i #1 reduced their hepatomegaly and cystogenesis, increased UDCA concentration, and inhibited HDAC6 activity in liver. In cystic cholangiocytes UDCA-HDAC6i #1 restored primary cilium length and exhibited potent antiproliferative activity. UDCA-HDAC6i #1 was actively transported into cells through BA and organic cation transporters. Conclusions: These UDCA-HDAC6i conjugates open a therapeutic avenue for PLDs.
Grants:	Instituto de Salud Carlos III PI15-01132 Instituto de Salud Carlos III PI18-01075 Instituto de Salud Carlos III CON14-00129 Instituto de Salud Carlos III PI14-00399 Instituto de Salud Carlos III PI17-00022 Instituto de Salud Carlos III PI16-00598 Ministerio de Economía y Competitividad RYC-2015-17755 Ministerio de Ciencia e Innovación BES-2014-069148 Ministerio de Ciencia e Innovación CTQ2016-80375-P Ministerio de Ciencia e Innovación CTQ2014-51912-REDC
Note:	Altres ajuts: Suported by IKERBASQUE, Basque foundation for Science (M.J. Perugorria and J.M. Banales), Spain; "Junta de Castilla y Leon" (J.J.G. Marin: SA06P17); "Diputación Foral Gipuzkoa" (J.M. Banales: DFG15/010, DFG16/004; M.J. Perugorria: DFG18/114, DFG19/081), BIOEF (Basque Foundation for Innovation and Health Research: EiTB Maratoia BIO15/CA/016/BD to J.M. Banales), Department of Health of the Basque Country (J.M. Banales: 2017111010; M.J. Perugorria: 2019111024), and Euskadi RIS3 (J.M. Banales: 2016222001, 2017222014, and 2018222029; 2019222054); La Caixa Scientific Foundation (J.M. Banales: HR17-00601); "Fundación Científica de la Asociación Española Contra el Cáncer" (AECC Scientific Foundation, to J.M. Banales and J.J.G. Marin); and "Centro Internacional sobre el Envejecimiento", Spain (J.J.G. Marin: OLD-HEPAMARKER, 0348-CIE-6-E). A. Santos-Laso by the Basque Government (PRE_2018_2_0195), and Pui Y. Lee-Law by the European Association for the Study of the Liver (EASL; Sheila Sherlock Award). Basque Government (F.P. Cossío: IT-324-07). I. Rivilla had a postdoctoral contract from the Donostia International Physics Center.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Published in:	Hepatology, 2020 , ISSN 1527-3350

DOI: 10.1002/hep.31216
PMID: 32145077

18 p, 2.4 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Josep Carreras Leukaemia Research Institute
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Articles > Published articles