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Synthetic Conjugates of Ursodeoxycholic Acid Inhibit Cystogenesis in Experimental Models of Polycystic Liver Disease
Author(s) -
CaballeroCamino Francisco J.,
Rivilla Ivan,
Herraez Elisa,
Briz Oscar,
SantosLaso Alvaro,
IzquierdoSanchez Laura,
LeeLaw Pui Y.,
Rodrigues Pedro M.,
MunozGarrido Patricia,
Jin Sujeong,
Peixoto Estanislao,
Richard Seth,
Gradilone Sergio A.,
Perugorria Maria J.,
Esteller Manel,
Bujanda Luis,
Marin Jose J.G.,
Banales Jesus M.,
Cossío Fernando P.
Publication year - 2021
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.31216
Subject(s) - ursodeoxycholic acid , polycystic liver disease , liver transplantation , pharmacology , conjugate , bile acid , medicine , cancer research , chemistry , transplantation , mathematical analysis , mathematics
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.